RhoA Signaling in Neurodegenerative Diseases

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [87] Gilkes, 2014, Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells, Proc. Natl. Acad. Sci. USA source
• Disputed

  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.

  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. sourceExperimental — accuracy not yet measured
• Disputed

  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.

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

In the paper

“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].”

What the sources say

• Disputed

  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.

  cites [179] Labandeira, 2020, Rho kinase inhibitor fasudil reduces l-DOPA-induced dyskinesia in a rat model of Parkinson’s disease, Br. J. Pharmacol. sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Results report increased hippocampal p75NTR in two HD mouse models and in postmortem samples from HD patients. The increase was hippocampal; the paper reports no corresponding cortical increase. (LLM, conf=0.94)

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

  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.

  cites [204] Plotkin, 2014, Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington’s disease, Neuron sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  In ‘RHOGDIs as negative regulators of RHO GTPases’ (page not provided), the review says RHOGDIs inhibit GDP release and can extract RHO proteins from membranes, holding them in the cytosol. It describes this inhibitory role as acting mostly on inactive RHO GTPases. (LLM, conf=0.92)

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

In the paper

“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].”

What the sources say

• Supported

  The Introduction (page not provided) states that GAPs activate the intrinsic GTPase activity of small GTPases, causing GTP hydrolysis to GDP and inorganic phosphate and inactivating the GTPase. (LLM, conf=0.94)

  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. source
• Supported

  Section 1.2 says small GTPases have intrinsically low GTPase activity, GAPs stimulate GTP hydrolysis, and the GDP-bound form is generally inactive. This supports the cited account of GAP-driven hydrolysis and inactivation; inorganic phosphate is the implied product of that hydrolysis. (LLM, conf=0.91)

  cites [14] Toma-Fukai, S., and Shimizu, T. (2019). Structural Insights into the Regulation Mechanism of Small GTPases by GEFs. Molecules, 24. source

In the paper

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

What the sources say

• Supported

  The Results section identifies FAM65A as a new RHO effector and shows that it binds active RHOA. The Discussion describes FAM65A as localising to the Golgi and cytoplasmic punctae. Page numbers are not provided in our copy. (LLM, conf=0.94)

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

In the paper

“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].”

What the sources say

• Supported

  The Results section on RhoA activity states that activation was assessed by binding to Rhotekin’s Rho-binding domain and that the S88E/T100E phosphomimetic bound more strongly than wild-type RhoA. The same section concludes that ERK phosphorylation of S88 and T100 enhances RhoA activity in response to EGF. (LLM, conf=0.94)

  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. source

In the paper

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

What the sources say

• Supported

  The section on negative regulation of RhoA by Mst3 phosphorylation states that an in vitro assay confirmed Mst3 phosphorylates RhoA at Ser26 (Fig. 6B). The Discussion also states this finding directly. (LLM, conf=0.95)

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

In the paper

“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].”

What the sources say

• Partly 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)

  cites [124] Bianchi, 2020, Of rings and spines: The multiple facets of Citron proteins in neural development, Small GTPases sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Abstract states that mDia produces actin filaments and ROCK activates myosin to cross-link them, inducing actomyosin bundles and contractility. The Fig. 2 caption in section 2 describes the same complementary mechanisms. Page numbers are not provided in our copy. (LLM, conf=0.95)

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

In the paper

“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].”

What the sources say

• Partly 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)

  cites [47] Roberts, 2008, Rho Family GTPase modification and dependence on CAAX motif-signaled posttranslational modification, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [48] Casey, 2005, Post-prenylation-processing enzymes as new targets in oncogenesis, Nat. Rev. Cancer source

In the paper

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

What the sources say

• Supported

  The Introduction states that mammals have only three genes encoding RHOGDIs and names RHOGDI1, RHOGDI2 and RHOGDI3. The section on regulation of RHOGDI–RHO GTPase interactions also refers to “the three mammalian RHOGDIs.” (LLM, conf=0.95)

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

In the paper

“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].”

What the sources say

• Partly 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)

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

In the paper

“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].”

What the sources say

• Supported

  The Introduction (page not available in our copy) states that Rhotekin’s Rho-binding domain selectively interacts with GTP-bound active Rho and inhibits both its intrinsic and GAP-enhanced GTPase activity. It also says the domain has been used to monitor activated Rho, supporting the citing sentence’s assay context. (LLM, conf=0.90)

  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. source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [4] DeGeer, 2013, Rho GTPases in neurodegeneration diseases, Exp. Cell Res. source
• Partly 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)

  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. sourceExperimental — accuracy not yet measured
• Partly 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)

  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. sourceExperimental — accuracy not yet measured
• Supported

  Section 3, “Functions of Rho GTPases in the Central Nervous System” (page not provided), links dysregulated Rho GTPase signaling to neurodegenerative disorders and describes RhoA activation after traumatic brain injury. The cancer-progression clause is attached to a different citation and is not attributed to this source. (LLM, conf=0.94)

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

In the paper

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

What the sources say

• Partly 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)

  cites [128] Mardakheh, 2016, RHO binding to FAM65A regulates Golgi reorientation during cell migration, J. Cell Sci. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Results section on TGF-β signalling reports that SMAD4 inactivation reduced RHOA mRNA in colon cancer cells and concludes that RHOA is a transcriptional target of SMAD4. The Results section on c-MYC and SP1 shows that SP1 sustains RHOA expression and that reduced c-MYC increases SP1 binding to the RHOA promoter; the Discussion explicitly states that c-MYC interferes with that binding and downregulates RHOA. (LLM, conf=0.94)

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

In the paper

“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.”

What the sources say

• Partly 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)

  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. sourceExperimental — accuracy not yet measured
• Supported

  Section 2.2 describes GEF-stimulated nucleotide exchange that produces GTP-bound small GTPases. Section 1.4 states that nucleotide exchange changes switch I and switch II, with the GTP-bound form being active. These passages support the attributed claim. (LLM, conf=0.93)

  cites [14] Toma-Fukai, S., and Shimizu, T. (2019). Structural Insights into the Regulation Mechanism of Small GTPases by GEFs. Molecules, 24. source

In the paper

“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].”

What the sources say

• Partly 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)

  cites [82] Kim, 2018, Regulation of RhoA GTPase and various transcription factors in the RhoA pathway, J. Cell. Physiol. sourceExperimental — accuracy not yet measured
• Partly 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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly 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)

  cites [1] Stankiewicz, 2014, Rho family GTPases: Key players in neuronal development, neuronal survival, and neurodegeneration, Front. Cell. Neurosci. sourceExperimental — accuracy not yet measured
• Partly 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)

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

In the paper

“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”

What the sources say

• Partly 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)

  cites [49] Lang, 1996, Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes, EMBO J. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [50] Ellerbroek, 2003, Serine phosphorylation negatively regulates RhoA in vivo, J. Biol. Chem. source
• Partly 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)

  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. sourceExperimental — accuracy not yet measured
• Partly 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)

  cites [51] Tkachenko, 2011, Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells, Nat. Cell Biol. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [55] Sawada, 2001, cGMP-dependent protein kinase phosphorylates and inactivates RhoA, Biochem. Biophys. Res. Commun. source
• ?Not checked — no full text of the sourcecites [52] Sauzeau, 2005, Phosphorylation of serine 188 protects RhoA from ubiquitin/proteasome-mediated degradation in vascular smooth muscle cells, Circ. Res. source

In the paper

“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].”

What the sources say

• Supported

  The Results report that miR-340 mimics significantly elongated melanocyte dendrites and negatively regulated RhoA expression. The paper also reports direct targeting of RhoA by miR-340, supporting the cited mechanism. (LLM, conf=0.94)

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

In the paper

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

What the sources say

• Supported

  The Results section, “SmgGDS Specifically Activates RhoA and RhoC,” reports nucleotide exchange for RhoA and RhoC but not other tested GTPases. The cell-assay passage likewise states that SmgGDS-558 activated RhoA and RhoC, but not RhoB. (LLM, conf=0.95)

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

In the paper

“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.”

What the sources say

• Partly supported

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

  cites [1] Stankiewicz, 2014, Rho family GTPases: Key players in neuronal development, neuronal survival, and neurodegeneration, Front. Cell. Neurosci. sourceExperimental — accuracy not yet measured
• Partly supported

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

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

In the paper

“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.”

What the sources say

• Partly 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)

  cites [128] Mardakheh, 2016, RHO binding to FAM65A regulates Golgi reorientation during cell migration, J. Cell Sci. sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Introduction states that FAM65A associates with GTP-bound RHOA and with CCM3, MST4, and MST3. The Results further describe CCM3 as an adaptor connecting FAM65A to MST proteins, supporting the claimed binding pathway without requiring direct FAM65A–MST binding. (LLM, conf=0.92)

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

In the paper

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

What the sources say

• Partly 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)

  cites [27] Ridley, 1993, rho family GTPase activating proteins p190, bcr and rhoGAP show distinct specificities in vitro and in vivo, EMBO J. sourceExperimental — accuracy not yet measured
• Partly 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)

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [126] Camera, 2003, Citron-N is a neuronal Rho-associated protein involved in Golgi organization through actin cytoskeleton regulation, Nat. Cell Biol. source
• Supported

  In “Cit-N associates with Golgi at spines,” the paper reports that Cit-N accumulates at dendritic spines and is abundantly associated with TGN38-positive membranes. It also reports colocalization with Golgi markers, supporting the attributed association with the Golgi complex. (LLM, conf=0.94)

  cites [127] Camera, 2008, The RhoA-associated protein Citron-N controls dendritic spine maintenance by interacting with spine-associated Golgi compartments, EMBO Rep. source

In the paper

“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].”

What the sources say

• Supported

  The Results section reports that XPLN stimulates exchange on RhoA and RhoB but not RhoC, and that changing RhoC’s isoleucine 43 to valine makes it a substrate. The Discussion identifies valine 43 in RhoA and RhoB versus isoleucine 43 in RhoC as an important determinant, while noting that other residues also contribute. (LLM, conf=0.93)

  cites [20] Arthur, 2002, XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC, J. Biol. Chem. source
• Supported

  The Introduction reports that XPLN catalyzed nucleotide exchange for RhoA and RhoB in vitro but showed little activity toward RhoC. The Introduction and Results identify Val43 in RhoA/B versus Ile43 in RhoC and show that swapping residue 43 changes XPLN activity, supporting the stated explanation. (LLM, conf=0.90)

  cites [21] Sloan, 2012, Divergence of Rho residue 43 impacts GEF activity, Small GTPases source

In the paper

“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.”

What the sources say

• Partly 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)

  cites [47] Roberts, 2008, Rho Family GTPase modification and dependence on CAAX motif-signaled posttranslational modification, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [48] Casey, 2005, Post-prenylation-processing enzymes as new targets in oncogenesis, Nat. Rev. Cancer source

In the paper

“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].”

What the sources say

• Supported

  The Results section, “Altered miR-185 levels contribute to structural alterations of Df(16)A+/− neurons” (Figures 6A–F; page not provided), reports that reducing miR-185 in primary hippocampal neurons decreased dendritic complexity and spine density. Citation [108] is attached to that finding; the proposed RhoA mechanism is associated with subsequent citations, not attributed to this source. (LLM, conf=0.94)

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

In the paper

“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].”

What the sources say

• Supported

  The Introduction states that SCF-FBXL19 targets both active and inactive RhoA. Results §3.3 identifies Lys135 as the ubiquitin-acceptor site, and §3.4 shows that Erk2 promotes RhoA phosphorylation and that inhibiting the Erk pathway attenuates FBXL19-mediated ubiquitination and degradation. Our copy provides section labels but no page numbers for these passages. (LLM, conf=0.90)

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

In the paper

“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].”

What the sources say

• Supported

  The Introduction states that Rho GTPases must dissociate from RhoGDI before activation because GEFs cannot act directly on the complex, and identifies GDI displacement factors as enabling that step. The section on factors affecting dissociation repeats the same sequence for RhoA. (LLM, conf=0.95)

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [41] Kim, 2017, RhoA GTPase oxidation stimulates cell proliferation via nuclear factor-κB activation, Free Radic. Biol. Med. source
• Partly 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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Results report that p115, p190, PRG (PDZ-RhoGEF), and LARG promote nucleotide exchange for RhoA, RhoB, and RhoC, but show no significant activity toward Rac1 or Cdc42. The Discussion likewise identifies these three Rho isoforms as their specific substrates. (LLM, conf=0.95)

  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. source

In the paper

“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].”

What the sources say

• Partly supported

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

  cites [118] Koch, 2018, ROCK inhibition in models of neurodegeneration and its potential for clinical translation, Pharmacol. Ther. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

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

  cites [120] Amano, 2010, Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity, Cytoskeleton sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The paper states that miR-133b is specifically expressed in midbrain dopaminergic neurons. Its expression analysis reports that miR-133b was enriched in midbrain relative to cortex or cerebellum and deficient in Parkinson’s disease patient samples (Figure 2A, p. 8). (LLM, conf=0.94)

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

In the paper

“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].”

What the sources say

• Supported

  The Introduction directly describes two classes of RhoA effectors and lists the same scaffold proteins and serine/threonine kinases. Its terms Dia, PRK1/PKNα, and ROCKI/ROCKII correspond to the citing sentence’s mDia, PKN, and ROCK. (LLM, conf=0.95)

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

In the paper

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

What the sources say

• Supported

  The section on antagonistic regulation of neuronal survival says that Rac typically promotes neuronal survival while Rho can induce neuronal apoptosis. The in vitro section specifically identifies RhoA activation as eliciting apoptosis in neuronal models, supporting the citing sentence’s use of RhoA. (LLM, conf=0.94)

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

In the paper

“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].”

What the sources say

• Partly 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)

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

In the paper

“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].”

What the sources say

• Supported

  The Discussion (passages 5 and 8; page numbers not provided) states that ROCK1 interacts with APP and phosphorylates it at Ser655. It also states that this phosphorylation promotes amyloidogenic APP processing by increasing BACE1–APP interaction. (LLM, conf=0.94)

  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 source

In the paper

“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].”

What the sources say

• Partly 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)

  cites [197] Pollitt, 2003, A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor, Neuron sourceExperimental — accuracy not yet measured
• Supported

  The paper’s introductory passage describes a FRET-based screen that identified Y-27632 as a ROCK inhibitor, and reports that it reduced Htt aggregation in cultured cells and Htt-mediated neurodegeneration in Drosophila. These are presented as findings from the authors’ earlier work; the Discussion also recounts reduced Htt aggregation and toxicity. (LLM, conf=0.94)

  cites [198] Shao, 2008, Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation, Mol. Cell. Biol. source

In the paper

“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.”

What the sources say

• Supported

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

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

In the paper

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

What the sources say

• Supported

  The paper’s opening summary (page not specified in our copy) states that ROCK inhibition reduces mutant huntingtin levels and aggregation through activation of the ubiquitin–proteasome system and macroautophagy. It also identifies Y-27632 as the ROCK inhibitor that reduces huntingtin aggregation and toxicity. (LLM, conf=0.93)

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

In the paper

“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).”

What the sources say

• Supported

  The Introduction identifies PPARγ, β-catenin, and HIF-1α among transcription factors regulated by RhoA. Section 3.6 describes RhoA-mediated STAT3 phosphorylation and nuclear translocation, completing the list in the claim. (LLM, conf=0.93)

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

In the paper

“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].”

What the sources say

• Supported

  The Abstract says mitochondrial movement in animal cells is primarily driven by microtubule-based motors. The Summary explains that neurons must both deliver mitochondria and retain them where energy production and calcium buffering are needed, supporting the cited paraphrase. (LLM, conf=0.90)

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

In the paper

“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].”

What the sources say

• Supported

  The Results section (“Inhibition of ROCK Enhances htt Degradation”; page unavailable) reports that Y-27632 treatment activated both the UPS and autophagy in Neuro2a cells. It also reports UPS activation after ROCK knockdown, with increased autophagy only when both ROCK1 and ROCK2 were silenced—not after knockdown of either isoform alone. (LLM, conf=0.89)

  cites [142] Bauer, 2009, Inhibition of Rho kinases enhances the degradation of mutant huntingtin, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [143] Mleczak, 2013, Regulation of autophagosome formation by Rho kinase, Cell. Signal. source
• Partly 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)

  cites [144] Koch, 2014, ROCK2 is a major regulator of axonal degeneration, neuronal death and axonal regeneration in the CNS, Cell Death Dis. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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. source
• Partly 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)

  cites [146] Hamano, 2020, Rho-kinase ROCK inhibitors reduce oligomeric tau protein, Neurobiol. Aging sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly 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)

  cites [186] Chacon, 2011, Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid beta toxicity, Mol. Neurodegener. sourceExperimental — accuracy not yet measured
• Partly 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)

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

In the paper

“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].”

What the sources say

• Supported

  The Introduction states that RhoA/ROCK signaling is essential for Aβ-induced chemotaxis, cytotoxicity, and inflammatory response in BV2 cells. The chemotaxis and inflammatory-response sections report suppression by Fasudil and Y27632; the cytotoxicity section reports significant protection at 10 µM Aβ. (LLM, conf=0.93)

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

In the paper

“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].”

What the sources say

• Partly 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)

  cites [139] Moskal, 2020, ROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway, Nat. Commun. sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  cites [1] Stankiewicz, 2014, Rho family GTPases: Key players in neuronal development, neuronal survival, and neurodegeneration, Front. Cell. Neurosci. sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Could 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)

  cites [185] Huesa, 2010, Altered distribution of RhoA in Alzheimer’s disease and AβPP overexpressing mice, J. Alzheimer’s Dis. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [155] Zhang, 2013, Rho kinase inhibitor fasudil regulates microglia polarization and function, Neuroimmunomodulation source
• Partly supported

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

  cites [156] Ding, 2010, Fasudil protects hippocampal neurons against hypoxia-reoxygenation injury by suppressing microglial inflammatory responses in mice, J. Neurochem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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. source

In the paper

“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].”

What the sources say

• Supported

  The Discussion (page not provided) explicitly hypothesizes that Aβ accumulation activates the RhoA/ROCK pathway, which then fuels further Aβ production. It describes escalation of this cycle as contributing to amyloid buildup, matching the citing sentence’s tentative framing. (LLM, conf=0.93)

  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. source

In the paper

“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].”

What the sources say

• Supported

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

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

In the paper

“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].”

What the sources say

• Supported

  The Results section, under “The inhibition of p75NTR-mediated RhoA/ROCK signaling rescues amyloid-induced changes in dendritic spine morphology,” reports that pretreatment with either TAT-Pep5 or Y-27632 protected primary hippocampal neurons from Aβ1–42 oligomer-induced loss of dendritic spine density. It identifies TAT-Pep5 as inhibiting p75NTR-mediated RhoA activation and Y-27632 as a ROCK inhibitor. (LLM, conf=0.95)

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

In the paper

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

What the sources say

• Supported

  The passage under Section 2.5 reports significantly increased RhoA activity in PARK2 KO neurons and says Rhosin reversed their enhanced migration. The concluding passage reports impaired neurite outgrowth and says both migration and neurite-outgrowth changes were reversible with RhoA inhibition. Page numbers are not provided in our copy. (LLM, conf=0.94)

  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. source

In the paper

“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].”

What the sources say

• Supported

  The Abstract reports that Fasudil improved motor and cognitive function in mice expressing human α-synuclein with the A53T mutation and significantly reduced midbrain α-synuclein pathology. The Conclusion identifies Fasudil as a ROCK inhibitor, while noting that its anti-aggregative effect also involves direct binding to α-synuclein. (LLM, conf=0.94)

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

In the paper

“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].”

What the sources say

• Supported

  The section “IKK γ Facilitates RhoA Activation” (page not provided) describes activated IKKβ phosphorylating IκB, followed by IκB degradation and NF-κB translocation to the nucleus to activate target-gene transcription. It identifies cytokines and chemokines among those targets, supporting the claim about proinflammatory factors. (LLM, conf=0.94)

  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. source

In the paper

“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].”

What the sources say

• Partly 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)

  cites [129] Lai, 2014, Excitotoxicity and stroke: Identifying novel targets for neuroprotection, Prog. Neurobio.l sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

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

  cites [167] Miralles, 2003, Actin dynamics control SRF activity by regulation of its coactivator MAL, Cell sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly 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)

  cites [188] Herskowitz, 2013, Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer’s disease mouse model, J. Neurosci. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Results section reports that fasudil reduced total, phosphorylated, and oligomeric tau in P301L mice. The Abstract and Results also describe reductions in pathological tau in cell models and activation of autophagy and proteasome pathways associated with tau degradation. The pathway findings are not presented as demonstrated mechanisms in the mice specifically. (LLM, conf=0.93)

  cites [146] Hamano, 2020, Rho-kinase ROCK inhibitors reduce oligomeric tau protein, Neurobiol. Aging source
• Partly 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)

  cites [190] Gentry, 2016, Rho Kinase Inhibition as a Therapeutic for Progressive Supranuclear Palsy and Corticobasal Degeneration, J. Neurosci. sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  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. sourceExperimental — accuracy not yet measured
• Partly 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)

  cites [183] Ostrowski, 2007, Statins reduce amyloid-beta production through inhibition of protein isoprenylation, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [187] Hamano, 2012, Pitavastatin decreases tau levels via the inactivation of Rho/ROCK, Neurobiol. Aging source
• ?Not checked — no full text of the sourcecites [224] Boimel, 2009, Statins reduce the neurofibrillary tangle burden in a mouse model of tauopathy, J. Neuropathol. Exp. Neurol. source

In the paper

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

What the sources say

• ?Could 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)

  cites [185] Huesa, 2010, Altered distribution of RhoA in Alzheimer’s disease and AβPP overexpressing mice, J. Alzheimer’s Dis. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

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

  cites [171] Barcia, 2012, ROCK/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo, Sci. Rep. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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. source
• ?Not checked — no full text of the sourcecites [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 source
• Partly supported

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

  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 sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

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

  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. sourceExperimental — accuracy not yet measured
• Supported

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

  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. source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [210] Hu, 2003, Protein kinase and protein phosphatase expression in the central nervous system of G93A mSOD over-expressing mice, J. Neurochem. source
• Partly 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)

  cites [212] Conti, 2014, Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients, Biochim. Biophys. Acta. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [163] Tonges, 2014, Rho kinase inhibition modulates microglia activation and improves survival in a model of amyotrophic lateral sclerosis, Glia source
• Supported

  The Discussion links ROCK activation to motor-neuron death in experimental ALS models and reports that inhibiting ROCK with fasudil reduced degeneration. The Introduction describes ROCK as mediating rho GTPase activity and says fasudil’s effects in ALS had not previously been established, consistent with the claim’s characterization of this as a less-studied therapeutic focus. (LLM, conf=0.87)

  cites [211] Takata, 2013, Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis, Br. J. Pharmacol. source

In the paper

“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].”

What the sources say

• Supported

  The Results passage [5] states that increased p75NTR levels were accompanied by long-term memory deficits, altered LTP, reduced synaptic proteins, decreased dendritic spine density, and RhoA hyperactivation. This directly supports the cited sentence in the Huntington’s disease context studied. (LLM, conf=0.95)

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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, Oncogene
• ?Not checked — no full text of the sourcecites [33] Leonard, 1992, The identification and characterization of a GDP-dissociation inhibitor (GDI) for the CDC42Hs protein, J. Biol. Chem. source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [37] Yamashita, 2003, The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI, Nat. Neurosci. source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [119] Arimura, 2004, Role of CRMP-2 in neuronal polarity, J. Neurobiol. source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [102] Niu, 2016, MiR-133b ameliorates axon degeneration induced by MPP+ via targeting RhoA, Neuroscience source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [102] Niu, 2016, MiR-133b ameliorates axon degeneration induced by MPP+ via targeting RhoA, Neuroscience source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [37] Yamashita, 2003, The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI, Nat. Neurosci. source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. source

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Piekny, 2005, Cytokinesis: Welcome to the Rho zone, Trends Cell Biol. source

In the paper

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

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [40] Kuhlmann, 2016, RhoGDIalpha Acetylation at K127 and K141 Affects Binding toward Nonprenylated RhoA, Biochemistry source