RhoA Signaling in Neurodegenerative Diseases

Probably not a substantial claim: may not pass S3 (load-bearing).

HIF-1α transcriptional activation of RHOA has consistently been reported across a number of different cell types, including breast cancer cells, cardiac myocytes, neuroblastoma cells, mesenchymal stem cells, and chondrocytes.

“In contrast, HIF-1α transcriptional activation of RHOA has consistently been reported across a number of different cell types, including breast cancer cells [87], cardiac myocytes [88], neuroblastoma cells [89], mesenchymal stem cells [90], and chondrocytes [91].”

• cites [87] Gilkes, 2014, Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells, Proc. Natl. Acad. Sci. USA sourceNot checked — no full text of the source
• cites [88] Falcon, 2015, Hypoxic induction of T-type Ca2+ channels in rat cardiac myocytes: Role of HIF-1α and RhoA/ROCK signalling, J. Physiol. sourceDisputed

  For the cardiac-myocyte citation, the Results (page not specified) report that constitutively active HIF-1α did not affect RhoA activity. The authors instead conclude that RhoA acts upstream of HIF-1α, contrary to the attributed direction of regulation. Their hypoxia-induced increase in RhoA does not establish HIF-1α transcriptional activation of RHOA. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [89] Yin, 2015, Upregulation of HIF-1α protects neuroblastoma cells from hypoxia-induced apoptosis in a RhoA-dependent manner, Mol. Med. Rep. sourceDisputed

  The cited paper’s ‘Hypoxia induces RhoA in PC12 cells’ section reports that hypoxia increased RhoA expression in neuroblastoma cells. Its RhoA-knockdown experiment found that reducing RhoA reduced hypoxia-induced HIF-1α expression—the opposite regulatory direction from the claimed HIF-1α activation of RHOA. The paper does not establish HIF-1α transcriptional activation of RHOA. (LLM, conf=0.85)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

ROCK inhibition using Fasudil reduces the development of L-DOPA-induced dyskinesia and inhibits already established dyskinesia affecting the therapeutic effect of L-DOPA.

“In 6-hydroxydopamine lesioned rats with dyskinesia, RhoA and ROCK were increased in the substantia nigra and striatum, and ROCK inhibition using Fasudil was found to reduce the development of L-DOPA-induced dyskinesia and to inhibit already established dyskinesia affecting the therapeutic effect of L-DOPA [179].”

• cites [179] Labandeira, 2020, Rho kinase inhibitor fasudil reduces l-DOPA-induced dyskinesia in a rat model of Parkinson’s disease, Br. J. Pharmacol. sourceDisputed

  The Discussion (section 4) supports the claim that fasudil reduced both the development of dyskinesia and already established dyskinesia. But it explicitly says this occurred without affecting the therapeutic effect of l-DOPA, contrary to the citing sentence’s statement that it affected that effect. The Results (section 3.2) likewise report that the motor benefit of l-DOPA was preserved. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

p75NTR is increased in HD mouse models and in postmortem samples from HD patients.

“p75NTR was increased in HD mouse models and in postmortem samples from HD patients [203,204].”

• cites [203] Brito, 2014, Neurotrophin receptor p75(NTR) mediates Huntington’s disease-associated synaptic and memory dysfunction, J. Clin. Investig. sourceSupported
• cites [204] Plotkin, 2014, Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington’s disease, Neuron sourceDisputed

  The Results section reports that p75NTR mRNA expression was not measurably different in the HD mouse neurons studied; the Discussion attributes increased p75NTR signaling to elevated PTEN, not increased p75NTR itself. The cited passages do not report p75NTR expression in postmortem samples from HD patients. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

GDIs prevent dissociation of GDP from the GTPase and retain inactive GDP-bound GTPases in the cytosol.

“Inactivation is further facilitated by guanine nucleotide dissociation inhibitors (GDIs) that prevent dissociation of GDP from the GTPase and thus retain the inactive GDP-bound GTPases in the cytosol.”

• cites [15] Boulter, 2011, The ‘invisible hand’: Regulation of RHO GTPases by RHOGDIs, Nat. Rev. Mol. Cell Biol. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

GAPs enhance the intrinsic GTPase activity of small GTPases, resulting in GTP hydrolysis to GDP and inorganic phosphate and inactivation of the GTPases.

“Conversely, GTPase-activating proteins (GAPs) enhance the relatively slow intrinsic GTPase activity of the small GTPases, resulting in GTP hydrolysis to GDP and inorganic phosphate (Pi) and inactivation of the GTPases [5,14].”

• cites [5] Arrazola Sastre, A., Luque Montoro, M., Galvez-Martin, P., Lacerda, H.M., Lucia, A.M., Llavero, F., and Zugaza, J.L. (2020). Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases. Int. J. Mol. Sci., 21. sourceSupported
• cites [14] Toma-Fukai, S., and Shimizu, T. (2019). Structural Insights into the Regulation Mechanism of Small GTPases by GEFs. Molecules, 24. sourceSupported

May combine two claims.

FAM65A is a novel RhoA effector protein associated with the Golgi complex.

“A novel RhoA effector protein FAM65A is also associated with the Golgi complex.”

• cites [128] Mardakheh, 2016, RHO binding to FAM65A regulates Golgi reorientation during cell migration, J. Cell Sci. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

ERK phosphorylates RhoA on Ser88 and Thr100, which upregulates RhoA activity as evaluated by its binding capacity to Rhotekin.

“Extracellular signal-related kinase (ERK) phosphorylates RhoA on Ser88 and Thr100, which has been reported to upregulate RhoA activity as evaluated by its binding capacity to the effector protein Rhotekin [61].”

• cites [61] Tong, J., Li, L., Ballermann, B., and Wang, Z. (2016). Phosphorylation and Activation of RhoA by ERK in Response to Epidermal Growth Factor Stimulation. PLoS ONE, 11. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Mst3 phosphorylates RhoA on Ser26.

“Mammalian Ste20-like kinase 3 (Mst3) phosphorylates RhoA on Ser26 [60].”

• cites [60] Tang, 2014, Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition, J. Neurosci. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Citron N is expressed only in postmitotic and fully differentiated neurons.

“While citron kinase is ubiquitously expressed in proliferating cells, the isoform citron N, which is also a scaffold protein for RhoA, is expressed only in postmitotic and fully differentiated neurons [124].”

• cites [124] Bianchi, 2020, Of rings and spines: The multiple facets of Citron proteins in neural development, Small GTPases sourcePartly supported

  The “Expression and localization of CIT proteins” section says CIT-N expression begins when cells become post-mitotic and reaches its highest levels in fully differentiated neurons. It does not say CIT-N is expressed only in neurons or only after full differentiation: the same section describes CIT-N in astrocytes and in early post-mitotic neurons. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

ROCK and mDia cooperate for actomyosin assembly and contractility, with mDia activation forming actin filaments and ROCK activating myosin to crosslink them.

“As mDia activation leads to the formation of actin filaments and ROCK activates myosin to crosslink them, ROCK and mDia cooperate for actomyosin assembly and contractility [122].”

• cites [122] Narumiya, 2009, Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion, Cancer Metastasis Rev. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

After prenylation, RhoA undergoes proteolytic removal of the last three C-terminal residues by RCE1 and methylation of Cys190 by ICMT at the endoplasmic reticulum.

“The prenylation step takes place in the cytosol and is followed by proteolytic removal of the last three C-terminal (AAX) residues by the protease RAS-converting enzyme 1 (RCE1) and methylation of the prenylated Cys190 by isoprenylcysteine carboxyl methyltransferase (ICMT) at the cytoplasmic surface of the endoplasmic reticulum (ER) [47,48].”

• cites [47] Roberts, 2008, Rho Family GTPase modification and dependence on CAAX motif-signaled posttranslational modification, J. Biol. Chem. sourcePartly supported

  The paper’s introductory description of CAAX processing says that prenylation is followed by Rce1 removal of the three AAX residues and Icmt methylation of the prenylated cysteine; its Rce1/Icmt processing section discusses these steps in relation to RhoA. The passages do not identify that cysteine as Cys190 or place the reactions at the cytoplasmic surface of the ER, so those specifics are not supported by this copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [48] Casey, 2005, Post-prenylation-processing enzymes as new targets in oncogenesis, Nat. Rev. Cancer sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Only three RhoGDIs have been described in mammals.

“In contrast to the vast number of known RhoGEFs and RhoGAPs, only three RhoGDIs have been described in mammals [15].”

• cites [15] Boulter, 2011, The ‘invisible hand’: Regulation of RHO GTPases by RHOGDIs, Nat. Rev. Mol. Cell Biol. sourceSupported

May combine two claims.

ROCK phosphorylates the myosin light chain subunit of myosin IIb, leading to actomyosin assembly and contractility, both through direct interaction and indirectly by ROCK-mediated inhibition of MLCP through phosphorylation of MYPT1.

“ROCK also phosphorylates the myosin light chain (MLC) subunit of the actin-based motor protein myosin IIb, leading to actomyosin assembly and contractility. This occurs both through a direct interaction and indirectly by ROCK-mediated inhibition of myosin light chain phosphatase (MLCP) through phosphorylation of its myosin phosphatase-targeting subunit 1 (MYPT1) [7].”

• cites [7] Mulherkar, S., and Tolias, K.F. (2020). RhoA-ROCK Signaling as a Therapeutic Target in Traumatic Brain Injury. Cells, 9. sourcePartly supported

  Section 2, “Rho GTPase Signaling” (page not provided), says ROCK increases MLC phosphorylation and actomyosin contractile force, both directly and through phosphorylation and inhibition of myosin phosphatase. It identifies the motor protein as myosin II, not specifically myosin IIb, and does not identify MYPT1 as the phosphorylated phosphatase subunit or explicitly describe actomyosin assembly. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Rhotekin binds GTP-bound RhoA and inhibits both the intrinsic and GAP-enhanced GTPase activity of RhoA.

“Interestingly, the RhoA scaffold effector protein Rhotekin binds GTP-bound RhoA and inhibits both the intrinsic and GAP-enhanced GTPase activity of RhoA; this is why it is widely used in pull-down assays for activated RhoA [31].”

• cites [31] Ito, H., Morishita, R., and Nagata, K.I. (2018). Functions of Rhotekin, an Effector of Rho GTPase, and Its Binding Partners in Mammals. Int. J. Mol. Sci., 19. sourceSupported

May combine two claims.

Dysregulation of Rho GTPases has been studied in relation to cancer progression, but accumulating evidence supports a role in traumatic brain injury and neurodegenerative diseases.

“Dysregulation of Rho GTPases has been studied in relation to cancer progression for a number of years [3], but accumulating evidence supports a role in traumatic brain injury and neurodegenerative diseases as well [4,5,6,7].”

• cites [4] DeGeer, 2013, Rho GTPases in neurodegeneration diseases, Exp. Cell Res. sourceNot checked — no full text of the source
• cites [5] Arrazola Sastre, A., Luque Montoro, M., Galvez-Martin, P., Lacerda, H.M., Lucia, A.M., Llavero, F., and Zugaza, J.L. (2020). Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases. Int. J. Mol. Sci., 21. sourcePartly supported

  Section 3, “Small GTPases of the Rho Family” (page not provided), says Rho GTPases play an important role in neurodegenerative processes, including those associated with Alzheimer’s and Parkinson’s diseases. Our copy does not address traumatic brain injury, so it supports only the neurodegenerative-disease part of the claim. The cancer-progression clause is attached to a different citation [3]. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [6] Kimura, T., Horikoshi, Y., Kuriyagawa, C., and Niiyama, Y. (2021). Rho/ROCK Pathway and Noncoding RNAs: Implications in Ischemic Stroke and Spinal Cord Injury. Int. J. Mol. Sci., 22. sourcePartly supported

  The Introduction links excessive Rho/ROCK activity to Parkinson’s and Alzheimer’s diseases, supporting the neurodegenerative-disease part of the claim. The paper discusses ischemic stroke and spinal cord injury, but the passages found do not address traumatic brain injury. The cancer clause is cited to a different source [3], so it is not part of this verdict. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [7] Mulherkar, S., and Tolias, K.F. (2020). RhoA-ROCK Signaling as a Therapeutic Target in Traumatic Brain Injury. Cells, 9. sourceSupported

May combine two claims.

The FAM65A/CCM3/MST relocation is essential for both membrane trafficking from the Golgi and orientation of the Golgi toward the leading edge of the cell.

“This is essential for both membrane trafficking from the Golgi and the orientation of the Golgi toward the leading edge of the cell [128].”

• cites [128] Mardakheh, 2016, RHO binding to FAM65A regulates Golgi reorientation during cell migration, J. Cell Sci. sourcePartly supported

  The Introduction and Discussion state that RHO-dependent relocation of the FAM65A–CCM3–MST complex is crucial for Golgi reorientation toward the leading edge. The Introduction discusses secretory traffic from the Golgi, but the paper does not establish that this complex’s relocation is essential for membrane trafficking from the Golgi. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

In colon cancer cells, SMAD4 and SP1 activated RHOA expression, while c-Myc interfered with SP1 binding to the RHOA promoter, downregulating RHOA expression.

“In colon cancer cells, the transcription factors SMAD family member 4 (SMAD4) and specific protein 1 (SP1) activated RHOA expression, while c-Myc was reported to interfere with the binding of SP1 to the RHOA promoter, leading to downregulation of RHOA expression [85].”

• cites [85] Dopeso, 2018, Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer, Br. J. Cancer sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

GEFs catalyze the exchange of GDP for GTP, leading to conformational changes in switch I and switch II regions required for activation of small GTPases.

“In response to extracellular stimuli emanating from cell surface receptors, guanine nucleotide exchange factors (GEFs) catalyze the exchange of GDP for GTP, leading to the conformational changes in the switch I and switch II regions required for activation of the small GTPases.”

• cites [5] Arrazola Sastre, A., Luque Montoro, M., Galvez-Martin, P., Lacerda, H.M., Lucia, A.M., Llavero, F., and Zugaza, J.L. (2020). Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases. Int. J. Mol. Sci., 21. sourcePartly supported

  The Introduction states that GEFs promote GDP release and GTP binding, shifting small GTPases from an inactive to an active state. It also places small GTPases in signaling responses to extracellular stimuli, but does not identify conformational changes in switch I and switch II as the mechanism of activation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [14] Toma-Fukai, S., and Shimizu, T. (2019). Structural Insights into the Regulation Mechanism of Small GTPases by GEFs. Molecules, 24. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Several transcription factors regulate RHOA expression, including c-Myc, Max, HIF-1α, NF-κB, and STAT6, together with several miRNAs.

“Several transcription factors have been shown to regulate RHOA expression, including c-Myc, Max, hypoxia-inducible factor 1 alpha (HIF-1α), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription 6 (STAT6), together with several reported miRNAs (Figure 2C) [82,83].”

• cites [82] Kim, 2018, Regulation of RhoA GTPase and various transcription factors in the RhoA pathway, J. Cell. Physiol. sourcePartly supported

  The Abstract and sections 2.3–2.4 support regulation of RhoA expression by c-Myc, HIF-1α, NF-κB, STAT6, and several miRNAs. The passages on transcriptional regulation describe a Myc–Skp2–Miz1–p300 complex, but do not identify Max as a regulator of RhoA expression. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [83] Nomikou, 2018, Transcriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: Implications for the pathogenesis of human diseases, Cell. Mol. Life Sci. sourcePartly supported

  The sections on transcriptional regulation of RhoA describe Myc, NF-κB, and STAT6 as regulators, and the miRNA section identifies several miRNAs that regulate RhoA expression (page numbers unavailable). The copy does not establish Max or HIF-1α as RhoA regulators; its hypoxia passage instead concerns HIF-3α regulation of RhoC. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

RhoA and many of its downstream effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells.

“RhoA and many of its downstream effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells.”

• Also stated in: § 3. Downstream Targets of RhoA · plain

  “RhoA and many of its effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells [1,117].”

• cites [1] Stankiewicz, 2014, Rho family GTPases: Key players in neuronal development, neuronal survival, and neurodegeneration, Front. Cell. Neurosci. sourcePartly supported

  The “Rho in Neuronal Development” section (page unavailable) describes roles for RhoA in neurons and radial glia, supporting the inference that its signaling matters in both. Neither that section nor the passages retrieved on expression state that RhoA and many downstream effectors are highly expressed throughout the nervous system; the expression findings concern specific injury conditions. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [117] Guiler, 2021, Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases, Front. Cell. Neurosci. sourcePartly supported

  The Introduction’s “Rho GTPase Subfamily” section describes RhoA’s effects on neuronal processes and reports that loss of RhoA in microglia led to synapse loss in mice. The “Small Molecules” section says the RhoA effector ROCK2 is mainly expressed in the brain and spinal cord. Neither passage establishes that RhoA and many of its downstream effectors are highly expressed throughout the nervous system; no page numbers are available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

PKA/PKG-mediated phosphorylation of RhoA on Ser188 inhibits RhoA activity by favoring interaction with RhoGDI, leading to extraction from the plasma membrane, and protects GTP-bound RhoA from ubiquitin-mediated proteasomal degradation.

“The most well-studied phosphorylation event of RhoA is protein kinase A (PKA) and cyclic GMP-dependent protein kinase (PKG)-mediated phosphorylation on Ser188, close to the prenylated Cys190 in the C-terminus [49,50,56]. This phosphorylation inhibits RhoA activity by favoring interaction with RhoGDI, leading to its extraction from the plasma membrane [50,51,55], and protects GTP-bound RhoA from ub”

• cites [49] Lang, 1996, Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes, EMBO J. sourcePartly supported

  The Results passages show that PKA phosphorylates RhoA at Ser188, increases RhoGDI binding to phosphorylated RhoA-GTP, and enables GDI to extract RhoA from membranes. The Discussion says this may terminate RhoA signalling, but explicitly states that the fate of phosphorylated RhoA-GTP was not investigated. Our copy does not establish PKG-mediated phosphorylation or protection from ubiquitin-mediated proteasomal degradation. Page numbers are unavailable in the indexed passages. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [50] Ellerbroek, 2003, Serine phosphorylation negatively regulates RhoA in vivo, J. Biol. Chem. sourceNot checked — no full text of the source
• cites [56] Sauzeau, 2000, Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle, J. Biol. Chem. sourcePartly supported

  The ‘cGK Phosphorylates RhoA in Vitro’ passage identifies Ser188 as the PKG phosphorylation site. The Discussion reports that PKG phosphorylation moves activated RhoA from the membrane to the cytosol and recounts earlier work linking PKA phosphorylation to increased RhoGDI interaction. Our copy does not address protection of GTP-bound RhoA from ubiquitin-mediated proteasomal degradation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [51] Tkachenko, 2011, Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells, Nat. Cell Biol. sourcePartly supported

  The Results section ('PKA Phosphorylation Regulates the Dynamics of RhoA Activation'; page unavailable) states that PKA phosphorylation of RhoA at Ser188 increases RhoGDI binding and reduces RhoA activity in part through sequestration from the membrane. The passages found do not establish PKG-mediated phosphorylation or protection of GTP-bound RhoA from ubiquitin-mediated proteasomal degradation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [55] Sawada, 2001, cGMP-dependent protein kinase phosphorylates and inactivates RhoA, Biochem. Biophys. Res. Commun. sourceNot checked — no full text of the source
• cites [52] Sauzeau, 2005, Phosphorylation of serine 188 protects RhoA from ubiquitin/proteasome-mediated degradation in vascular smooth muscle cells, Circ. Res. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

miR-340 promotes dendrite extension through suppressing RhoA expression in melanocytes.

“Another RhoA-targeting miRNA linked to dendrite formation is miR-340, which has been shown to promote dendrite extension through suppressing RhoA expression in melanocytes [113].”

• cites [113] Jian, 2014, MicroRNA 340 is involved in UVB-induced dendrite formation through the regulation of RhoA expression in melanocytes, Mol. Cell. Biol. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

SmgGDS specifically activates RhoA and RhoC but not RhoB.

“Another example is SmgGDS, which specifically activates RhoA and RhoC but not RhoB [22].”

• cites [22] Hamel, 2011, SmgGDS is a guanine nucleotide exchange factor that specifically activates RhoA and RhoC, J. Biol. Chem. sourceSupported

May combine two claims.

Many neuronal studies support the general model that Rac and Cdc42 stimulate neuronal growth cone dynamics, dendritic spine formation, and axonal extension and guidance, while RhoA inhibits these processes and causes axonal and dendritic retraction and spine and synapse loss.

“Many neuronal studies support the general model that Rac and Cdc42 stimulate these processes, while RhoA inhibits them and causes axonal and dendritic retraction and spine and synapse loss.”

• cites [1] Stankiewicz, 2014, Rho family GTPases: Key players in neuronal development, neuronal survival, and neurodegeneration, Front. Cell. Neurosci. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [7] Mulherkar, S., and Tolias, K.F. (2020). RhoA-ROCK Signaling as a Therapeutic Target in Traumatic Brain Injury. Cells, 9. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Upon binding to RhoA, the FAM65A/CCM3/MST complex relocates away from the Golgi complex to the cytoplasmic membrane, relieving the inhibitory effect of MST4 on Golgi reorientation.

“Upon binding to RhoA, the FAM65A/CCM3/MST complex relocates away from the Golgi complex to the cytoplasmic membrane, relieving the inhibitory effect of MST4 on Golgi reorientation.”

• cites [128] Mardakheh, 2016, RHO binding to FAM65A regulates Golgi reorientation during cell migration, J. Cell Sci. sourcePartly supported

  The Discussion (page unavailable) proposes that RHO–GTP binding to FAM65A relocates the FAM65A–CCM3–MST complex from the Golgi, relieving MST-mediated inhibition of Golgi reorientation. The Results identify the destination as cytoplasmic punctae, likely vesicular compartments, not the ‘cytoplasmic membrane’ specified in the claim. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Activated RhoA binds FAM65A, which in turn binds CCM3 and MST.

“Activated RhoA binds FAM65A, which in turn binds cerebral cavernous malformation-3 protein (CCM3) and the interacting mammalian STE20-like protein kinase (MST).”

• cites [128] Mardakheh, 2016, RHO binding to FAM65A regulates Golgi reorientation during cell migration, J. Cell Sci. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

p190-RhoGAP inactivates RhoA and not Cdc42 and Rac1, but does not differentiate among RhoA, RhoB, and RhoC.

“For example, p190-RhoGAP inactivates RhoA and not Cdc42 and Rac1 [27], but it does not differentiate among RhoA, RhoB, and RhoC [28].”

• cites [27] Ridley, 1993, rho family GTPase activating proteins p190, bcr and rhoGAP show distinct specificities in vitro and in vivo, EMBO J. sourcePartly supported

  The in vitro results report that p190GAP is ninefold more effective against rho than against rac or G25K, supporting a preference for rho but not the claim that it does not act on Rac1. The same section says p190GAP has some capacity to down-regulate all three tested proteins. The RhoA/RhoB/RhoC comparison is attached to a different citation [28], so it is not assessed here. (LLM, conf=0.91)

  Experimental — accuracy not yet measured
• cites [28] Thomas, 2011, Src and caveolin-1 reciprocally regulate metastasis via a common downstream signaling pathway in bladder cancer, Cancer Res. sourcePartly supported

  Citation [28] is attached to the claim that p190-RhoGAP does not differentiate among RhoA, RhoB, and RhoC. The Results section reports that p190RhoGAP knockdown increased activation of both RhoA and RhoC in RT4 cells, but it does not assess RhoB. The separate claim about Cdc42 and Rac1 is attached to [27], not this source. No page number is available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Citron N is enriched in dendritic spines and is associated with the endomembrane system, in particular the Golgi complex.

“Citron N is enriched in dendritic spines and is associated with the endomembrane system, in particular the Golgi complex, where it maintains Golgi architecture by modulating local actin polymerization together with ROCK [126,127].”

• cites [126] Camera, 2003, Citron-N is a neuronal Rho-associated protein involved in Golgi organization through actin cytoskeleton regulation, Nat. Cell Biol. sourceNot checked — no full text of the source
• cites [127] Camera, 2008, The RhoA-associated protein Citron-N controls dendritic spine maintenance by interacting with spine-associated Golgi compartments, EMBO Rep. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

XPLN shows activity toward RhoA and RhoB but not RhoC due to an amino acid difference (Ile43 vs. Val43) at the N-terminus of the Rho isoforms.

“One example is XPLN, which shows activity toward RhoA and RhoB but not RhoC due to an amino acid difference (Ile43 vs. Val43) at the N-terminus of the Rho isoforms [20,21].”

• cites [20] Arthur, 2002, XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC, J. Biol. Chem. sourceSupported
• cites [21] Sloan, 2012, Divergence of Rho residue 43 impacts GEF activity, Small GTPases sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Prenylation of RhoA is catalyzed by GGTase-I, which transfers the geranylgeranyl moiety from geranylgeranyl pyrophosphate produced by the mevalonate pathway.

“This step is catalyzed by the geranylgeranyltransferase enzyme I (GGTase-I), which transfers the geranylgeranyl moiety from geranylgeranyl pyrophosphate, produced as a product of the mevalonate pathway involved in cholesterol synthesis, to RhoA.”

• cites [47] Roberts, 2008, Rho Family GTPase modification and dependence on CAAX motif-signaled posttranslational modification, J. Biol. Chem. sourcePartly supported

  The paper identifies RhoA as a GGTase-I substrate in the section on prenyltransferase specificity. It also describes GGTase-I adding a geranylgeranyl group and uses GGPP in its GGTase-I assays. The passages do not state that GGPP is produced by the mevalonate pathway involved in cholesterol synthesis; that part of the attributed claim is unsupported. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [48] Casey, 2005, Post-prenylation-processing enzymes as new targets in oncogenesis, Nat. Rev. Cancer sourceNot checked — no full text of the source

May combine two claims.

Reduced miR-185 expression caused deficits in dendritic complexity and spine development in hippocampal neurons, possibly mediated by increased RhoA expression.

“The reduced miR-185 expression caused deficits in dendritic complexity and spine development in hippocampal neurons [108], possibly mediated by increased RhoA expression as the two validated miR-185 targets, RhoA and Cdc42 [109], have altered expression levels in schizophrenia [110,111,112].”

• cites [108] Xu, 2013, Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion, Cell sourceSupported

May combine two claims.

SCFFBXL19 targets both the active and inactive forms of RhoA on Lys135, but the process is dependent on prior Erk2-mediated phosphorylation of RhoA.

“In contrast, SCFFBXL19 targets both the active and inactive forms of RhoA on Lys135, but the process is dependent on prior Erk2-mediated phosphorylation of RhoA [62].”

• cites [62] Wei, 2013, A new mechanism of RhoA ubiquitination and degradation: Roles of SCF(FBXL19) E3 ligase and Erk2, Biochim. Biophys. Acta. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Before a GTPase can be activated by GEFs, it needs to be dissociated from GDI because GEFs cannot directly act on the GTPase-GDI complex.

“Before the GTPase can be activated by GEFs, it needs to be dissociated from the GDI as GEFs cannot directly act on the GTPase–GDI complex. This step is facilitated by GDI displacement factors (GDFs) (Figure 2A) [16].”

• cites [16] Choi, 2020, Regulation of RhoA GTPase and novel target proteins for ROCK, Small GTPases sourceSupported

May combine two claims.

Cys16/20 oxidation of RhoA leads to RhoA activation by reducing the affinity of RhoA toward RhoGDI and increasing the association with the RhoA-specific GEF Vav2.

“More recently, however, it was reported that Cys16/20 oxidation of RhoA leads to RhoA activation by reducing the affinity of RhoA toward RhoGDI and increasing the association with the RhoA-specific GEF Vav2 [41,71].”

• cites [41] Kim, 2017, RhoA GTPase oxidation stimulates cell proliferation via nuclear factor-κB activation, Free Radic. Biol. Med. sourceNot checked — no full text of the source
• cites [71] Aghajanian, A., Wittchen, E.S., Campbell, S.L., and Burridge, K. (2009). Direct activation of RhoA by reactive oxygen species requires a redox-sensitive motif. PLoS ONE, 4. sourcePartly supported

  The Results section (Figure 4) shows that peroxide activates wild-type RhoA but not the C16/20A mutant, supporting a role for these cysteines in ROS-mediated activation. The paper does not report that oxidation reduces RhoA’s affinity for RhoGDI or increases its association with Vav2. Its Discussion instead describes nucleotide exchange after oxidation and reduction, noting that activation can occur without GEFs. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

p115-RhoGEF, p190-RhoGEF, LARG, and PDZ-RhoGEF activate the Rho isoforms RhoA, RhoB, and RhoC but no other Rho family members such as Rac1 and Cdc42.

“The RhoGEFs p115-RhoGEF, p190-RhoGEF, leukemia-associated RhoGEF (LARG), and PSD-95/Disc-large/ZO-1 homology (PDZ)-RhoGEF are more specific as they activate the Rho isoforms RhoA, RhoB, and RhoC but no other Rho family members such as Rac1 and Cdc42 [19].”

• cites [19] Jaiswal, 2011, Mechanistic insights into specificity, activity, and regulatory elements of the regulator of G-protein signaling (RGS)-containing Rho-specific guanine nucleotide exchange factors (GEFs) p115, PDZ-RhoGEF (PRG), and leukemia-associated RhoGEF (LARG), J. Biol. Chem. sourceSupported

May combine two claims.

In most cell types, the effect of RhoA on cytoskeletal dynamics is primarily mediated by its activation of ROCK, which via phosphorylation and activation of LIMK increases the phosphorylation and inactivation of cofilin 1 to stabilize actin filaments, leading to reduced actin turnover and inhibition of neurite outgrowth.

“In most cell types, the effect of RhoA on cytoskeletal dynamics is primarily mediated by its activation of ROCK, which via phosphorylation and activation of LIM kinase (LIMK) increases the phosphorylation and inactivation of cofilin 1 (an actin-depolymerizing and severing factor) to stabilize actin filaments. This leads to reduced actin turnover and inhibition of neurite outgrowth [118].”

• cites [118] Koch, 2018, ROCK inhibition in models of neurodegeneration and its potential for clinical translation, Pharmacol. Ther. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

MAP2, tau, and neurofilament are neuron-specific substrates for ROCK, and their microtubule polymerizing activity and neurofilament assembly are inhibited by ROCK-mediated phosphorylation, leading to inhibition of neurite elongation and shortened neurites.

“MAP2, tau, and neurofilament are also neuron-specific substrates for ROCK, and their microtubule polymerizing activity and neurofilament assembly are inhibited by ROCK-mediated phosphorylation, leading to inhibition of neurite elongation and shortened neurites [120].”

• cites [120] Amano, 2010, Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity, Cytoskeleton sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

miR-133b is enriched in midbrain dopaminergic neurons and was found to be deficient in the parkinsonian midbrain.

“miR-133b is enriched in midbrain dopaminergic neurons and was found to be deficient in the parkinsonian midbrain [101].”

• cites [101] Kim, 2007, A MicroRNA feedback circuit in midbrain dopamine neurons, Science sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Effector proteins for RhoA fall primarily into two classes: scaffold proteins such as rhophilin, rhotekin, kinectin, and mDia, and serine/threonine protein kinases such as PKN, citron kinase, and ROCK.

“The effector proteins for RhoA described so far fall primarily into two classes: scaffold proteins such as rhophilin, rhotekin, kinectin, and mammalian diaphanous-related formin (mDia) and serine/threonine protein kinases such as protein kinase N (PKN), citron kinase, and ROCK [116].”

• cites [116] Amin, 2013, Rho-kinase: Regulation, (dys)function, and inhibition, Biol. Chem. sourceSupported

May combine two claims.

Rac typically promotes neuronal survival, while RhoA induces neuronal apoptosis.

“Similar to their opposing effects on cytoskeletal dynamics, Rac typically promotes neuronal survival, while RhoA induces neuronal apoptosis [1].”

• cites [1] Stankiewicz, 2014, Rho family GTPases: Key players in neuronal development, neuronal survival, and neurodegeneration, Front. Cell. Neurosci. sourceSupported

May combine two claims.

Ser188 phosphorylation inhibits RhoA binding to its effector ROCK but does not affect binding to rhotekin and mDia, thereby specifically inhibiting RhoA/ROCK signaling.

“Furthermore, Ser188 phosphorylation has been found to inhibit RhoA binding to its effector protein Rho-associated coiled-coil-containing kinase (ROCK) but does not affect its binding to other RhoA effector proteins, including rhotekin and mammalian diaphanous (mDia), thereby specifically inhibiting RhoA/ROCK signaling [53,54].”

• cites [53] Takemoto, K., Ishihara, S., Mizutani, T., Kawabata, K., and Haga, H. (2015). Compressive stress induces dephosphorylation of the myosin regulatory light chain via RhoA phosphorylation by the adenylyl cyclase/protein kinase A signaling pathway. PLoS ONE, 10. sourcePartly supported

  The Results section on RhoA activation and phosphorylation (page not provided) says Ser188-phosphorylated RhoA cannot interact with or activate ROCK. The paper uses rhotekin to assay active RhoA and discusses mDia1 signaling, but it does not establish that Ser188 phosphorylation leaves binding to either effector unaffected. Thus the claimed selectivity for ROCK over those effectors is not supported. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [54] Nusser, 2006, Serine phosphorylation differentially affects RhoA binding to effectors: Implications to NGF-induced neurite outgrowth, Cell. Signal. sourceNot checked — no full text of the source

May combine two claims.

ROCK directly interacts with APP and phosphorylates its Ser655 residue, promoting amyloidogenic processing of APP by increasing the interaction of BACE1 with APP.

“It was recently reported that ROCK directly interacts with APP and phosphorylates its Ser655 residue, promoting amyloidogenic processing of APP by increasing the interaction of β-site APP cleaving enzyme 1 (BACE1) with APP [194].”

• cites [194] Hu, 2019, Rho-associated coiled-coil kinase 1 activation mediates amyloid precursor protein site-specific Ser655 phosphorylation and triggers amyloid pathology, Aging Cell sourceSupported

May combine two claims.

From an in vitro screen for molecules that reduce polyglutamine toxicity, the ROCK-inhibitor Y27632 was identified and subsequently shown to reduce Htt aggregation in cultured cells and Htt-mediated neurodegeneration in drosophila.

“From an in vitro screen for molecules that reduce polyglutamine toxicity, the ROCK-inhibitor Y27632 was identified and subsequently shown to reduce Htt aggregation in cultured cells and Htt-mediated neurodegeneration in drosophila [197,198].”

• cites [197] Pollitt, 2003, A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor, Neuron sourcePartly supported

  The High-Throughput Screening passage describes identifying Y-27632 in a cellular screen for reduced polyglutamine aggregation, not toxicity. It reports reduced htt exon 1 aggregation in cultured cells, while the Drosophila-model passage reports protection against photoreceptor-neuron loss caused by htt exon 1(Q93). (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [198] Shao, 2008, Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation, Mol. Cell. Biol. sourceSupported

May combine two claims.

A high-throughput screen of approximately 3000 compounds in HEK293 cells identified several ROCK inhibitors that increased the recruitment of parkin to damaged mitochondria, leading to increased targeting of mitochondria to lysosomes and removal of damaged mitochondria.

“A recent high-throughput screen of ~3000 compounds in HEK293 cells identified several ROCK inhibitors that increased the recruitment of parkin to damaged mitochondria, leading to increased targeting of mitochondria to lysosomes and removal of damaged mitochondria from the cells.”

• cites [139] Moskal, 2020, ROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway, Nat. Commun. sourceSupported

May combine two claims.

The mechanism of Y27632-mediated reduction of Htt toxicity involves an increase in both proteasomal degradation of Htt and macroautophagy.

“The mechanism was later found to involve Y27632-mediated increase in both proteasomal degradation of Htt and macroautophagy [200].”

• cites [200] Bauer, 2009, Enhanced degradation of mutant huntingtin by rho kinase inhibition is mediated through activation of proteasome and macroautophagy, Autophagy sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Other transcription factors regulated by RhoA include PPARγ, β-catenin, STAT3, and HIF-1α.

“Other transcription factors regulated by RhoA include peroxisome proliferator-activated receptor γ (PPARγ), β-catenin, signal transducer and activator of transcription-3 (STAT3), and hypoxia inducible factor-1α (HIF-1α).”

• cites [82] Kim, 2018, Regulation of RhoA GTPase and various transcription factors in the RhoA pathway, J. Cell. Physiol. sourceSupported

May combine two claims.

The cellular distribution of mitochondria is controlled both by their translocation along the microtubule system and by their retention at specific metabolically active sites within the cell.

“The cellular distribution of mitochondria is controlled both by their translocation along the microtubule system and by their retention at specific metabolic active sites within the cell [137].”

• cites [137] Schwarz, 2013, Mitochondrial trafficking in neurons, Cold Spring Harb. Perspect. Biol. sourceSupported

May combine two claims.

Inhibition of ROCK or direct downregulation of ROCK expression results in activation of both autophagy and the UPS, indicating that RhoA/ROCK signaling negatively regulates degradation pathways.

“Several studies have shown that inhibition of ROCK or direct downregulation of ROCK expression results in the activation of both autophagy and the UPS, indicating that RhoA/ROCK signaling negatively regulates the degradation pathways [142,143,144,145,146].”

• cites [142] Bauer, 2009, Inhibition of Rho kinases enhances the degradation of mutant huntingtin, J. Biol. Chem. sourceSupported
• cites [143] Mleczak, 2013, Regulation of autophagosome formation by Rho kinase, Cell. Signal. sourceNot checked — no full text of the source
• cites [144] Koch, 2014, ROCK2 is a major regulator of axonal degeneration, neuronal death and axonal regeneration in the CNS, Cell Death Dis. sourcePartly supported

  The Results section reports increased autophagic flux in retinal ganglion cells after ROCK2-shRNA downregulation, supporting the autophagy part of the claim. It does not report activation of the ubiquitin–proteasome system (UPS); its reference to ubiquitinated substrates explains the role of p62 in assessing autophagy, not UPS activity. The Discussion also notes a study in which ROCK inhibition impaired a starvation-mediated autophagic response, so the claim is too broad about ROCK inhibition generally. No page number is available in our copy. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [145] Liu, 2016, Fasudil, a Rho kinase inhibitor, promotes the autophagic degradation of A53T α-synuclein by activating the JNK 1/Bcl-2/beclin 1 pathway, Brain Res. sourceNot checked — no full text of the source
• cites [146] Hamano, 2020, Rho-kinase ROCK inhibitors reduce oligomeric tau protein, Neurobiol. Aging sourcePartly supported

  The Results section, “ROCK inhibitors upregulated autophagy and activated proteasome,” reports that ROCK inhibitor treatment increased autophagy markers and 20S and 26S proteasome activity. The Discussion reports increased autophagic flux after ROCK knockdown, but does not report UPS activation after direct downregulation of ROCK expression. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Aβ activates RhoA by binding to p75NTR, and inhibition of this receptor or RhoA directly prevents the deleterious effects of Aβ in hippocampal neurons.

“Aβ activates RhoA by binding to the p75 neurotrophin receptor (p75NTR), and inhibition of this receptor or RhoA directly prevents the deleterious effects of Aβ in hippocampal neurons [186,196].”

• cites [186] Chacon, 2011, Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid beta toxicity, Mol. Neurodegener. sourcePartly supported

  The Discussion states that Aβ activates RhoA by binding to p75NTR. The Results show that inhibiting p75NTR signalling or RhoA counteracts Aβ’s effects in cultured hippocampal neurons, but TAT-pep5 rescued only around half the neurons from Aβ-induced death. Thus, saying the interventions prevent the deleterious effects without qualification overstates the survival result (page numbers unavailable in our copy). (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [196] Patnaik, 2020, Signaling via the p75 neurotrophin receptor facilitates amyloid-β-induced dendritic spine pathology, Sci. Rep. sourcePartly supported

  The Results sections on RhoA activation and dendritic spine morphology report that Aβ1–42 activates RhoA in p75NTR-competent hippocampal cultures, and that p75NTR deletion or blocking its downstream signaling protects against Aβ-induced spine changes. The paper tested a peptide that inhibits p75NTR-mediated RhoA activation and an inhibitor of ROCK, not direct inhibition of RhoA. Its demonstrated protection concerns dendritic spine pathology, rather than all deleterious effects of Aβ. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

RhoA/ROCK signaling is essential for Aβ-induced chemotaxis, cytotoxicity, and inflammatory response of BV2 microglia, and ROCK inhibition by Fasudil or Y27632 suppresses these inflammatory responses.

“RhoA/ROCK signaling was found to be essential for Aβ-induced chemotaxis, cytotoxicity, and inflammatory response of BV2 microglia, and ROCK inhibition by Fasudil or Y27632 could efficiently suppress these inflammatory responses [153].”

• cites [153] Zhang, 2019, Involvement of RhoA/ROCK Signaling in Aβ-Induced Chemotaxis, Cytotoxicity and Inflammatory Response of Microglial BV2 Cells, Cell. Mol. Neurobiol. sourceSupported

May combine two claims.

The ROCK inhibitor SR3677 was the most efficient at increasing parkin recruitment, and its neuroprotective effect was verified in vivo in a fly PD model subjected to paraquat.

“The inhibitor SR3677 was the most efficient, and its neuroprotective effect was verified in vivo in a fly PD model subjected to paraquat, a parkinsonian toxin that induces mitochondrial damage [139].”

• cites [139] Moskal, 2020, ROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway, Nat. Commun. sourcePartly supported

  The Results section on in vivo effects reports that SR3677 improved survival and climbing ability in paraquat-treated flies. But the Results section on Parkin recruitment says SR3677 ranked lower than other ROCK inhibitors in the screen; it does not support calling SR3677 the most efficient at increasing recruitment. Page numbers were not supplied in our copy. (LLM, conf=0.92)

  Experimental — accuracy not yet measured

May combine two claims.

RhoA can induce apoptosis via direct activation of MAPK p38 and JNK signaling pathways, which induce apoptosis through activation of proapoptotic Bcl-2 family members Bad and Bax.

“Furthermore, RhoA can induce apoptosis via direct activation of the mitogen-activated protein kinases (MAPK) p38 and c-Jun N-terminal kinase (JNK) signaling pathways, which induce apoptosis through activation of proapoptotic Bcl-2 family members, e.g., Bad and Bax [1] (Figure 3).”

• cites [1] Stankiewicz, 2014, Rho family GTPases: Key players in neuronal development, neuronal survival, and neurodegeneration, Front. Cell. Neurosci. sourcePartly supported

  The Figure 2 caption in the section on antagonistic Rac and Rho signaling says Rho can provoke apoptosis through p38- or JNK-dependent pathways that activate pro-apoptotic Bcl-2 family proteins. The copy does not say RhoA directly activates those kinases or identify Bad and Bax as the proteins activated by those pathways; it names Bad and Bax in connection with their inhibition by Rac/Akt. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

In APP-overexpressing transgenic mouse brains, RhoA expression is decreased within synapses but increased in degenerating neurites.

“Moreover, in Aβ precursor protein (APP)-overexpressing transgenic mouse brains, RhoA expression was decreased within synapses but increased in degenerating neurites [185], suggesting that RhoA mislocation is related to neurodegeneration.”

• cites [185] Huesa, 2010, Altered distribution of RhoA in Alzheimer’s disease and AβPP overexpressing mice, J. Alzheimer’s Dis. sourceCould not verify

  The available copy shows the title (p. 1) and supplementary findings about synaptophysin, PSD95, and PAK in APP mice (p. 2), but no findings about RhoA within synapses or degenerating neurites. Searches for RhoA expression and synaptic or neuritic redistribution returned no decisive passage; the apparent absence of the main results prevents verification. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

May combine two claims.

ROCK inhibition shifts microglia from their proinflammatory M1 phenotype toward the anti-inflammatory M2 phenotype by inhibiting NF-κB activity and expression of proinflammatory cytokines IL-1β, IL-6, and TNFα, while increasing expression of the anti-inflammatory cytokine IL-10.

“Interestingly, ROCK inhibition has been reported to shift microglia from their proinflammatory M1 phenotype toward the anti-inflammatory M2 phenotype by inhibiting NF-кB activity and expression of the proinflammatory cytokines IL-1β, IL-6, and TNFα, while increasing the expression of the anti-inflammatory cytokine IL-10 [155,156,157].”

• cites [155] Zhang, 2013, Rho kinase inhibitor fasudil regulates microglia polarization and function, Neuroimmunomodulation sourceNot checked — no full text of the source
• cites [156] Ding, 2010, Fasudil protects hippocampal neurons against hypoxia-reoxygenation injury by suppressing microglial inflammatory responses in mice, J. Neurochem. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [157] He, 2016, Inhibition of Rho-kinase by Fasudil protects dopamine neurons and attenuates inflammatory response in an intranasal lipopolysaccharide-mediated Parkinson’s model, Eur. J. Neurosci. sourceNot checked — no full text of the source

May combine two claims.

Increased RhoA/ROCK activation promotes increased Aβ production, which in turn potentiates RhoA/ROCK activation and enhances Aβ build-up, forming a positive feedback loop.

“This is suggestive of a positive feedback loop where increased RhoA/ROCK activation promotes increased Aβ production, which in turn potentiates RhoA/ROCK activation and enhances the Aβ build-up [191].”

• cites [191] Henderson, 2016, Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer’s disease and ROCK1 depletion reduces amyloid-β levels in brain, J. Neurochem. sourceSupported

May combine two claims.

ROCK inhibition in an APP/presenilin-1 transgenic mouse model improves learning and memory impairment, accompanied by reduced tau phosphorylation, expression of Aβ and BACE1, and increased expression of synapse-associated proteins and neurotrophic factors in the hippocampus and cortex.

“ROCK inhibition in an APP/presenilin-1 (PS1) transgenic mouse model showed improved learning and memory impairment, accompanied by reduced tau phosphorylation, expression of Aβ and BACE1, and increased expression of synapse-associated proteins and neurotrophic factors in the hippocampus and cortex area of the brain [192].”

• cites [192] Gu, 2018, Therapeutic effect of Rho kinase inhibitor FSD-C10 in a mouse model of Alzheimer’s disease, Exp. Ther. Med. sourceSupported

May combine two claims.

Inhibition of p75NTR-mediated RhoA activation with the TAT-Pep5 peptide or Y-27632-mediated ROCK inhibition protects against oligomeric Aβ-induced spine loss in hippocampal neurons.

“Inhibition of p75NTR-mediated RhoA activation with the TAT-Pep5 peptide or Y-27632-mediated ROCK inhibition protected against oligomeric Aβ-induced spine loss in hippocampal neurons [196].”

• cites [196] Patnaik, 2020, Signaling via the p75 neurotrophin receptor facilitates amyloid-β-induced dendritic spine pathology, Sci. Rep. sourceSupported

May combine two claims.

Increased RhoA activity in PARK2 mutant neurons alters migration and impairs neuritogenesis, which can be rescued by Rhosin-mediated RhoA inhibition.

“Increased RhoA activity was found to alter migration and impair neuritogenesis, which could be rescued by Rhosin-mediated RhoA inhibition [178].”

• cites [178] Bogetofte, 2019, Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation, Neurobiol. Dis. sourceSupported

May combine two claims.

In vivo, ROCK inhibition using Fasudil decreases midbrain α-synuclein pathology and improves motor and cognitive functions in a transgenic mouse model expressing human α-synuclein with the A53T PD mutation.

“In vivo, ROCK inhibition using Fasudil was shown to decrease midbrain α-synuclein pathology and improve motor and cognitive functions in a transgenic mouse model expressing human α-synuclein with the A53T PD mutation [175].”

• cites [175] Tatenhorst, 2016, Fasudil attenuates aggregation of alpha-synuclein in models of Parkinson’s disease, Acta Neuropathol. Commun. sourceSupported

May combine two claims.

Activated IKKβ phosphorylates IκB, leading to its degradation and release of NF-κB that translocates to the nucleus and activates transcription of proinflammatory factors.

“Activated IKKβ then phosphorylates the inhibitor of NF-кB (IкB), leading to its degradation and release of NF-кB that translocates to the nucleus and activates transcription of proinflammatory factors [39].”

• cites [39] Kim, 2014, IκB kinase γ nuclear factor-κB-essential modulator (IKKγ/NEMO) facilitates RhoA GTPase activation, which, in turn, activates Rho-associated KINASE (ROCK) to phosphorylate IKKbeta in response to transforming growth factor (TGF)- β1, J. Biol. Chem. sourceSupported

May combine two claims.

ROCK can phosphorylate and activate PTEN, a negative regulator of PI3K/Akt, initiating apoptosis through released Akt suppression of proapoptotic Bcl-2 family proteins.

“ROCK can phosphorylate and activate phosphatase and tensin homologue (PTEN), which is a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway initiating apoptosis through released Akt suppression of proapoptotic Bcl-2 family proteins [129].”

• cites [129] Lai, 2014, Excitotoxicity and stroke: Identifying novel targets for neuroprotection, Prog. Neurobio.l sourcePartly supported

  Section 3.1.1 states that PTEN terminates PI3K–Akt signaling and mediates apoptotic effects. Section 3.1 says Akt inhibits the proapoptotic BCL-2 family member BAD. Neither passage supports the claim that ROCK phosphorylates and activates PTEN; the copy describes NMDAR-related regulation of PTEN instead. Page numbers were not available in the indexed passages. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

RhoA-mediated actin polymerization through ROCK/LIMK or mDia reduces the interaction between actin and MKL-1, inhibiting the actin-dependent nuclear export of MKL-1, which results in its nuclear accumulation and enhanced SRF-mediated transcription.

“RhoA-mediated actin polymerization through ROCK/LIMK or mDia reduces the interaction between actin and MLK-1, thus inhibiting the actin-dependent nuclear export of MKL-1, which results in its nuclear accumulation and enhanced SRF-mediated transcription [167].”

• cites [167] Miralles, 2003, Actin dynamics control SRF activity by regulation of its coactivator MAL, Cell sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Selective inhibition of the ROCK2 isoform, the most abundantly expressed ROCK isoform in the brain, suppresses BACE1 activity and reduces Aβ levels in cellular and animal models of AD.

“In line with this, a study found that selective inhibition of the ROCK2 isoform, the most abundantly expressed ROCK isoform in the brain, suppressed BACE1 activity and thereby reduced Aβ levels in cellular and animal models of AD.”

• cites [188] Herskowitz, 2013, Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer’s disease mouse model, J. Neurosci. sourcePartly supported

  The section “SR3677 reduces BACE1 activity and Aβ in 5XFAD mouse brain” reports reduced BACE1 activity in cells and mouse brain, reduced Aβ in mice, and suggests that BACE1 suppression contributes to the Aβ reduction. The Introduction also reports reduced Aβ production in cellular and animal models. Our copy does not establish that ROCK2 is the most abundantly expressed ROCK isoform in the brain, and it describes BACE1 suppression as one of multiple mechanisms rather than the sole cause. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

ROCK inhibition mitigates tau pathology both in vitro and in vivo by reducing total tau levels, tau phosphorylation, and oligomerization as well as facilitating tau degradation through autophagy and proteasome pathways.

“Tau is a substrate for phosphorylation by ROCK [181], and ROCK inhibition was found to mitigate tau pathology both in vitro and in vivo by reducing total tau levels, tau phosphorylation, and oligomerization as well as facilitating tau degradation through autophagy and proteasome pathways [146,190].”

• cites [146] Hamano, 2020, Rho-kinase ROCK inhibitors reduce oligomeric tau protein, Neurobiol. Aging sourceSupported
• cites [190] Gentry, 2016, Rho Kinase Inhibition as a Therapeutic for Progressive Supranuclear Palsy and Corticobasal Degeneration, J. Neurosci. sourcePartly supported

  The Results (page unavailable) report reduced tau in cultured neurons and a Drosophila model, reduced phosphorylated tau in cultured neurons, and findings consistent with autophagy-mediated tau degradation. They do not report reduced tau oligomerization. The Results also state that blocking the proteasome did not alter tau levels in ROCK-knockdown cells, so this paper does not support the claimed proteasome pathway. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

Several studies have demonstrated that statin-mediated RhoA/ROCK inhibition reduces NFT formation and decreases Aβ production.

“Indeed, several studies have demonstrated that statin-mediated RhoA/ROCK inhibition reduces NFT formation and decreases Aβ production [182,183,187,224].”

• cites [182] Pedrini, S., Carter, T.L., Prendergast, G., Petanceska, S., Ehrlich, M.E., and Gandy, S. (2005). Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLoS Med., 2. sourcePartly supported

  The Introduction (page unavailable) reports that statins decrease Aβ release in cultured rat hippocampal neurons, and the Discussion links statin-activated APP shedding in cultured cells to Rho/ROCK signaling. The paper does not report reduced NFT formation, nor does it demonstrate that RhoA/ROCK inhibition causes the reported decrease in Aβ release. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [183] Ostrowski, 2007, Statins reduce amyloid-beta production through inhibition of protein isoprenylation, J. Biol. Chem. sourcePartly supported

  The H4-cell results (indexed copy, section labeled Abstract; no page given) report that statins and Rho-family inhibition decreased Aβ secretion. The passages do not report reduced neurofibrillary tangle (NFT) formation or establish ROCK inhibition as the mechanism, so those parts of the attributed claim are unsupported. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [187] Hamano, 2012, Pitavastatin decreases tau levels via the inactivation of Rho/ROCK, Neurobiol. Aging sourceNot checked — no full text of the source
• cites [224] Boimel, 2009, Statins reduce the neurofibrillary tangle burden in a mouse model of tauopathy, J. Neuropathol. Exp. Neurol. sourceNot checked — no full text of the source

May combine two claims.

Overall RhoA levels are reduced in human AD brains, while remaining RhoA colocalizes with hyperphosphorylated tau in NFTs.

“Overall RhoA levels were reduced in human AD brains, while remaining RhoA colocalized with hyperphosphorylated tau in NFTs [185].”

• cites [185] Huesa, 2010, Altered distribution of RhoA in Alzheimer’s disease and AβPP overexpressing mice, J. Alzheimer’s Dis. sourceCould not verify

  Our indexed copy contains a title page (p. 1) and supplementary captions about APP mice (p. 2), but no findings on RhoA levels in human AD brains or RhoA colocalization with hyperphosphorylated tau in NFTs. Searches for those terms returned no relevant passage; the decisive main-text findings appear to be missing from the indexed copy. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

May combine two claims.

The neuroprotective effect of ROCK inhibition in MPTP models is attributed to inhibition of the MPTP-induced microglial inflammatory response and to a direct protective effect on the dopaminergic neuritic network in vitro and the striatal axonal innervation in vivo.

“The neuroprotective effect was attributed to inhibition of the MPTP-induced microglial inflammatory response [171,173,174] and to a direct protective effect on the dopaminergic neuritic network in vitro and the striatal axonal innervation in vivo [172,174].”

• cites [171] Barcia, 2012, ROCK/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo, Sci. Rep. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [173] Joglar, 2012, Involvement of microglial RhoA/Rho-kinase pathway activation in the dopaminergic neuron death. Role of angiotensin via angiotensin type 1 receptors, Neurobiol. Dis. sourceNot checked — no full text of the source
• cites [174] Borrajo, 2014, Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death, Neuropharmacology sourceNot checked — no full text of the source
• cites [172] Tonges, 2012, Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson’s disease, Brain sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Dopamine D2 receptor stimulation by dopamine acts in synergy with mutant Htt to increase aggregate formation, neuritic retraction, and striatal death through activation of the RhoA/ROCK/cofilin pathway, which can be reversed by ROCK inhibition.

“Dopamine D2 receptor stimulation by dopamine has been found to act in synergy with mutant Htt to increase aggregate formation, neuritic retraction, and striatal death through activation of the RhoA/ROCK/cofilin pathway, which could be reversed by ROCK inhibition [201,209].”

• cites [201] Deyts, C., Galan-Rodriguez, B., Martin, E., Bouveyron, N., Roze, E., Charvin, D., Caboche, J., and Betuing, S. (2009). Dopamine D2 receptor stimulation potentiates PolyQ-Huntingtin-induced mouse striatal neuron dysfunctions via Rho/ROCK-II activation. PLoS ONE, 4. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [209] Martin, 2017, Coupling of D2R Short but not D2R Long receptor isoform to the Rho/ROCK signaling pathway renders striatal neurons vulnerable to mutant huntingtin, Eur. J. Neurosci. sourceSupported

May combine two claims.

Activation of the RhoA/ROCK pathway has been implicated in the pathogenesis of ALS, although studied to a lesser degree and focusing on the disease-modifying effects of ROCK inhibition.

“Activation of the RhoA/ROCK pathway has also been implicated in the pathogenesis of ALS, although studied to a lesser degree and focusing on the disease-modifying effects of ROCK inhibition.”

• cites [210] Hu, 2003, Protein kinase and protein phosphatase expression in the central nervous system of G93A mSOD over-expressing mice, J. Neurochem. sourceNot checked — no full text of the source
• cites [212] Conti, 2014, Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients, Biochim. Biophys. Acta. sourcePartly supported

  Section 3.4 reports higher ROCK2 expression in skeletal muscle from ALS patients, supporting an association between ROCK signaling and ALS. The Discussion does not establish increased ROCK activity or a pathogenic role for pathway activation, and the paper does not report disease-modifying effects of ROCK inhibition. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [163] Tonges, 2014, Rho kinase inhibition modulates microglia activation and improves survival in a model of amyotrophic lateral sclerosis, Glia sourceNot checked — no full text of the source
• cites [211] Takata, 2013, Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis, Br. J. Pharmacol. sourceSupported

May combine two claims.

Increased p75NTR levels are accompanied by long-term memory deficits, altered LTP, reduced levels of synaptic proteins, decreased dendritic spine density, and increased activation of RhoA.

“Increased p75NTR levels were accompanied by long-term memory deficits, altered LTP, reduced levels of synaptic proteins, decreased dendritic spine density, and increased activation of RhoA [203].”

• cites [203] Brito, 2014, Neurotrophin receptor p75(NTR) mediates Huntington’s disease-associated synaptic and memory dysfunction, J. Clin. Investig. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Citron K is required for late cytokinesis stages of abscission.

“While mDia regulates actin polymerization and formation of the contractile ring, ROCK phosphorylates MLC and MYPT1 to activate myosin for furrow ingression, and citron K is required for late cytokinesis stages of abscission [123].”

• cites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

ROCK phosphorylates MLC and MYPT1 to activate myosin for furrow ingression.

“While mDia regulates actin polymerization and formation of the contractile ring, ROCK phosphorylates MLC and MYPT1 to activate myosin for furrow ingression, and citron K is required for late cytokinesis stages of abscission [123].”

• cites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

RhoGDI-1 is the most abundantly expressed RhoGDI and interacts with Rac1, Cdc42, RhoA, and RhoC, but not RhoB.

“RhoGDI-1 is the most abundantly expressed, and it interacts with several Rho GTPases, including Rac1 and Cdc42, and the Rho isoforms RhoA and RhoC, but not RhoB [32,33].”

• cites [32] Fukumoto, 1990, Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins, OncogeneNot checked — no full text of the source
• cites [33] Leonard, 1992, The identification and characterization of a GDP-dissociation inhibitor (GDI) for the CDC42Hs protein, J. Biol. Chem. sourceNot checked — no full text of the source

May combine two claims.

p75NTR directly binds RhoGDI-1 and initiates RhoA activation by releasing RhoA from RhoGDI-1.

“For example, the neurotrophin receptor p75NTR directly binds the RhoGDI-1 and initiates RhoA activation by releasing RhoA from RhoGDI-1 [37].”

• cites [37] Yamashita, 2003, The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI, Nat. Neurosci. sourceNot checked — no full text of the source

May combine two claims.

ROCK-mediated phosphorylation of CRMP-2 impairs its ability to bind tubulin and induces growth cone collapse.

“ROCK-mediated phosphorylation of CRMP-2 impairs its ability to bind tubulin and induces growth cone collapse [119].”

• cites [119] Arimura, 2004, Role of CRMP-2 in neuronal polarity, J. Neurobiol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

mDia regulates actin polymerization and formation of the contractile ring.

“While mDia regulates actin polymerization and formation of the contractile ring, ROCK phosphorylates MLC and MYPT1 to activate myosin for furrow ingression, and citron K is required for late cytokinesis stages of abscission [123].”

• cites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. sourceNot checked — no full text of the source

May combine two claims.

In an MPP+-induced cell culture PD model, miR-133b was significantly reduced, while RhoA protein levels were upregulated.

“In an MPP+-induced cell culture PD model, miR-133b was significantly reduced, while RhoA protein levels were upregulated [102].”

• cites [102] Niu, 2016, MiR-133b ameliorates axon degeneration induced by MPP+ via targeting RhoA, Neuroscience sourceNot checked — no full text of the source

May combine two claims.

Overexpression of miR-133b promoted neurite outgrowth of primary dopaminergic neurons and ameliorated axon degeneration caused by MPP+ by post-transcriptional inhibition of RhoA.

“Overexpression of miR-133b promoted neurite outgrowth of primary dopaminergic neurons and was able to ameliorate the axon degeneration caused by MPP+ by post-transcriptional inhibition of RhoA.”

• cites [102] Niu, 2016, MiR-133b ameliorates axon degeneration induced by MPP+ via targeting RhoA, Neuroscience sourceNot checked — no full text of the source

May combine two claims.

The p75NTR-RhoGDI-1 complex formation is strengthened by Nogo and MAG for neurite outgrowth inhibition, while NGF interferes with the binding between p75NTR and RhoGDI-1 to stimulate neurite outgrowth.

“Interestingly, the p75NTR-RhoGDI-1 complex formation has been found strengthened by the myelin-derived protein Nogo and myelin-associated glycoprotein (MAG) for neurite outgrowth inhibition, while the neurotrophin nerve growth factor (NGF) interferes with the binding between p75NTR and RhoGDI-1 that stimulates neurite outgrowth [37].”

• cites [37] Yamashita, 2003, The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI, Nat. Neurosci. sourceNot checked — no full text of the source

May combine two claims.

Citron kinase phosphorylates MLC, di-phosphorylates it at Thr18 and Ser19, and causes a different localization of myosin in the furrow, particularly at late stages of cytokinesis.

“Similarly to ROCK, citron kinase phosphorylates MLC, but it di-phosphorylates it at Thr18 and Ser19 and causes a different localization of myosin in the furrow, particularly at late stages of cytokinesis [123].”

• cites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. sourceNot checked — no full text of the source

May combine two claims.

Collectively, RhoA signaling actions drive neurite retraction and loss of spines and synapses.

“Collectively, these actions of RhoA signaling drive neurite retraction and loss of spines and synapses (Figure 3).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Active RhoA drives contraction of the contractile ring through stimulation of MLC phosphorylation.

“Active RhoA promotes the formation and stabilization of the cleavage furrow through its control of actin polymerization and drives the contraction of the contractile ring through its stimulation of MLC phosphorylation.”

• cites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

RhoA signaling regulates many fundamental cellular processes that rely on cytoskeletal organization.

“In summary, RhoA signaling regulates many fundamental cellular processes that rely on the cytoskeletal organization (Figure 3).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Acetylation of RhoGDI-1 on Lys127 and Lys141 reduces its binding to RhoA.

“For example, acetylation of RhoGDI-1 on Lys127 and Lys141 was recently shown to reduce its binding to RhoA [40].”

• cites [40] Kuhlmann, 2016, RhoGDIalpha Acetylation at K127 and K141 Affects Binding toward Nonprenylated RhoA, Biochemistry sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Citron kinase regulates proper spindle orientation by promoting nucleation and stability of astral microtubules.

“Citron kinase also regulates proper spindle orientation by promoting nucleation and stability of astral microtubules.”

• cites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

ROCK regulates autophagosome formation via PI3K and the JNK/Bcl-2/Beclin 1/Vps34 pathway.

“The exact downstream targets of RhoA/ROCK responsible for this effect are still not fully elucidated, but it has been suggested that ROCK regulates autophagosome formation via PI3K and the JNK/Bcl-2/Beclin 1/Vps34 pathway [145].”

• cites [145] Liu, 2016, Fasudil, a Rho kinase inhibitor, promotes the autophagic degradation of A53T α-synuclein by activating the JNK 1/Bcl-2/beclin 1 pathway, Brain Res. sourceNot checked — no full text of the source

May combine two claims.

ROCK inhibition reduces reactive gliosis and increases astrocytic expression of prosurvival genes.

“In astrocytes, RhoA/ROCK signaling plays a major role in determining astrocyte morphology and reactive state [118,160,161], and ROCK inhibition reduces reactive gliosis and increases astrocytic expression of prosurvival genes [162,163].”

• cites [162] Lau, 2012, Transcriptomic profiling of astrocytes treated with the Rho kinase inhibitor fasudil reveals cytoskeletal and pro-survival responses, J. Cell. Physiol. sourceNot checked — no full text of the source
• cites [163] Tonges, 2014, Rho kinase inhibition modulates microglia activation and improves survival in a model of amyotrophic lateral sclerosis, Glia sourceNot checked — no full text of the source

May combine two claims.

Accumulating evidence supports a role for RhoA signaling in Aβ aggregation, tau phosphorylation, neuroinflammation, and synaptic damage in AD.

“Accumulating evidence supports a role for RhoA signaling in Aβ aggregation, tau phosphorylation, neuroinflammation, and synaptic damage in AD [223].”

• cites [223] Cai, 2021, Role of RhoA/ROCK signaling in Alzheimer’s disease, Behav. Brain Res. sourceNot checked — no full text of the source

May combine two claims.

In primary rat hippocampal and dopaminergic neuronal cultures treated with rotenone, RhoA activity is increased and associated with reduced neurite outgrowth, which is normalized by ROCK inhibition using Y27632.

“In primary rat hippocampal and dopaminergic neuronal cultures treated with the neurotoxic pesticide rotenone, RhoA activity was increased and associated with reduced neurite outgrowth, which was normalized by ROCK inhibition using Y27632 [169].”

• cites [169] Sanchez, 2008, Rotenone-induced toxicity is mediated by Rho-GTPases in hippocampal neurons, Toxicol. Sci. sourceNot checked — no full text of the source