Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

May combine two claims.

Rlip+/− mice show cognitive impairments, increased oxidative stress, and mitochondrial abnormalities, features similar to late-onset AD.

“Recently, we reported that mice with a heterozygous loss of Rlip (Rlip+/−) showed cognitive impairments, increased oxidative stress, and mitochondrial abnormalities, features similar to those seen in late-onset AD [14].”

• cites [14] Awasthi, S., Hindle, A., Sawant, N.A., George, M., Vijayan, M., Kshirsagar, S., Morton, H., Bunquin, L.E., Palade, P.T., and Lawrence, J.J. (2021). RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease. Cells, 10. sourcePartly supported

  The Discussion (section 4, page not available) reports cognitive deficits, reduced antioxidant-enzyme activity, and altered mitochondrial dynamics in Rlip+/− mice, and compares these features with AD mouse models. The Introduction distinguishes late-onset sporadic AD from early-onset familial AD, but the paper does not specifically establish that the mice’s features resemble late-onset AD rather than AD more generally. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

Mitochondrial ROS can trigger production of amyloid β, which can in turn further damage mitochondria.

“There is also evidence that mitochondrial ROS can trigger the production of amyloid β, which can in turn further damage mitochondria [66,67], providing an additional layer to positive feedback models.”

• cites [66] Leuner, 2012, Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation, Antioxid. Redox Signal. sourceSupported
• cites [67] Reddy, 2008, Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer’s disease, Trends Mol. Med. sourcePartly supported

  The Introduction’s “Aβ and mitochondrial dysfunction” section reports that amyloid β can cause mitochondrial dysfunction and increase ROS production. Its “Biochemical changes” section says mitochondrial oxidative stress occurs before Aβ pathology, but does not say that mitochondrial ROS triggers Aβ production. The proposed feedback loop is therefore only partly supported. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

RalA and RalB promote clearance of dysfunctional mitochondria by mitophagy; following depolarization they relocalize to mitochondria and activate TBK1.

“It has also been found that RalA and RalB promote the clearance of dysfunctional mitochondria from the cell by mitophagy. Following the depolarization of a mitochondria, RalA and RalB relocalize to the mitochondria where they activate TBK1 which in turn promotes mitophagy [50].”

• cites [50] Pollock, S.R., Schinlever, A.R., Rohani, A., Kashatus, J.A., and Kashatus, D.F. (2019). RalA and RalB relocalization to depolarized mitochondria depends on clathrin-mediated endocytosis and facilitates TBK1 activation. PLoS ONE, 14. sourcePartly supported

  The Results section (‘RalA and RalB negatively regulate TBK1 activity’) reports that RalA and RalB relocalize after depolarization and that this relieves their inhibition of TBK1, allowing its activity to increase. The Introduction says Ral may be involved in mitophagy, but the paper does not show that RalA and RalB promote clearance of dysfunctional mitochondria by mitophagy. It also describes release of TBK1 inhibition, rather than direct activation by RalA and RalB. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

4-HNE can reach levels as high as 1 μM in normal human plasma; concentrations as high as 100 μM have been observed near the site of lipid peroxidation.

“4-HNE can reach levels as high as 1 µM in normal human plasma [72]; however, concentrations as high as 100 µM have been observed near the site of lipid peroxidation [57].”

• cites [72] Dygas, 1998, Is the glutathione conjugate of trans-4-hydroxy-2-nonenal transported by the multispecific organic anion transporting-ATPase of human erythrocytes?, Acta. Biochim. Pol. sourceSupported
• cites [57] Dalleau, 2013, Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance, Cell. Death Differ sourceSupported

May combine two claims.

Under stress, Rlip and HSF1 dissociate, freeing Rlip to catalyze ATP-dependent efflux of glutathione conjugates and xenobiotics and freeing HSF1 to translocate to the nucleus to activate stress response pathways.

“Under stress, Rlip and HSF1 dissociate [31,38], freeing Rlip to catalyze the ATP-dependent efflux of glutathione conjugates and xenobiotics and freeing HSF1 to translocate to the nucleus to activate stress response pathways [31,38].”

• cites [31] Hu, 2003, HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo, J. Biol. Chem. sourcePartly supported

  The Results and Abstract report that HSF1 dissociates from RalBP1 after heat shock, moves into the nucleus, and activates HSP70 transcription. Our copy does not say that dissociation frees RalBP1 to catalyze ATP-dependent efflux of glutathione conjugates or xenobiotics. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [38] Singhal, 2008, Hsf-1 and POB1 induce drug sensitivity and apoptosis by inhibiting Ralbp1, J. Biol. Chem. sourcePartly supported

  The introduction reports that stress releases Hsf-1 from its complex with Ralbp1, allowing Hsf-1 to enter the nucleus, and describes Ralbp1’s ATP-dependent efflux of xenobiotics and glutathione conjugates. It presents the further claim that stress-induced dissociation frees Ralbp1’s efflux activity as a model prediction, rather than an established consequence of stress. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

Stress induces Rlip translocation to the nucleus, suggesting Rlip may have a role in transcriptional regulation.

“Interestingly, Singhal et al. reported that stress also induces Rlip translocation to the nucleus, suggesting that Rlip may also have a role in transcriptional regulation [38].”

• cites [38] Singhal, 2008, Hsf-1 and POB1 induce drug sensitivity and apoptosis by inhibiting Ralbp1, J. Biol. Chem. sourceSupported

May combine two claims.

In the unstressed state, HSF1 and Rlip are mutually inhibitory, with HSF1 inhibiting Rlip efflux and Rlip sequestering HSF1 in the cytosol.

“In the unstressed state, HSF1 and Rlip are mutually inhibitory, with HSF1 inhibiting the efflux function of Rlip, and Rlip sequestering HSF1 in the cytosol.”

• cites [31] Hu, 2003, HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo, J. Biol. Chem. sourcePartly supported

  The Results (page unavailable) show that RalBP1 binds repressed HSF1 at 37 °C and that HSF1 is released and moves into the nucleus after heat shock. This supports the unstressed-state interaction and cytosolic retention, but our copy does not say that HSF1 inhibits RalBP1’s efflux function; a search for “efflux” found no such result. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [38] Singhal, 2008, Hsf-1 and POB1 induce drug sensitivity and apoptosis by inhibiting Ralbp1, J. Biol. Chem. sourcePartly supported

  In “Hsf-1 and POB1 Inhibit Ralbp1” (page not provided), the paper reports that Hsf-1 inhibits Ralbp1 transport and describes an unstressed cytoplasmic complex containing both proteins. It proposes mutual inhibition, including Ralbp1 inhibition of Hsf-1 activity, as a model rather than establishing it as an unqualified fact. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

Glutathione peroxidase activity decreased in Rlip+/− mice, indicating loss of mitochondrial function.

“Consistently, the activity of glutathione peroxidase, a mitochondrial antioxidant enzyme, decreased in the Rlip+/− mice, which also indicates a loss of mitochondrial function [14].”

• cites [14] Awasthi, S., Hindle, A., Sawant, N.A., George, M., Vijayan, M., Kshirsagar, S., Morton, H., Bunquin, L.E., Palade, P.T., and Lawrence, J.J. (2021). RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease. Cells, 10. sourcePartly supported

  The Discussion reports significantly reduced glutathione peroxidase activity in Rlip+/− mice compared with age-matched wildtype mice, alongside mitochondrial abnormalities. But the assay measured activity in brain homogenates (Methods, §2.8), and the paper does not establish that the decrease itself indicates a loss of mitochondrial function. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

Phosphorylation of RalA by Aurora A kinase localizes RalA and Rlip to mitochondria, where Rlip scaffolds cyclin B/Cdk1 to phosphorylate and recruit Drp1.

“Phosphorylation of RalA by Aurora A kinase localizes RalA and Rlip to the mitochondria, where Rlip serves as a scaffold to recruit cyclin B/Cdk1 to the mitochondria, where they in turn phosphorylate and recruit the mitochondrial fission protein Drp1 [22].”

• cites [22] Kashatus, 2011, RALA and RALBP1 regulate mitochondrial fission at mitosis, Nat. Cell. Biol. sourceSupported

May combine two claims.

Rlip+/− mice have significant increases in dentate gyrus and hippocampus expression of Drp1 and Fis1, and decreased expression of MFN1.

“Our recent findings show that heterozygous Rlip KO (Rlip+/−) mice have significant increases in the dentate gyrus and hippocampus expression of Drp1 and Fis1, genes involved with mitochondrial fission, and decreased expression of the mitofusin MFN1 [14].”

• cites [14] Awasthi, S., Hindle, A., Sawant, N.A., George, M., Vijayan, M., Kshirsagar, S., Morton, H., Bunquin, L.E., Palade, P.T., and Lawrence, J.J. (2021). RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease. Cells, 10. sourcePartly supported

  Section 3.4.1 (p. 16) reports significantly increased hippocampal Drp1 and Fis1 immunoreactivity and significantly reduced Mfn1 in Rlip+/− mice relative to wild-type mice. The copy does not identify a separate dentate gyrus result, so that more specific location is not established. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

Rlip shows stress-responsive changes in activity and binds to p53 and HSF1.

“Rlip shows stress-responsive changes in activity [31] and has been found to bind to the master stress-response transcription factors p53 and HSF1 (heat shock factor 1) [31,35].”

• cites [31] Hu, 2003, HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo, J. Biol. Chem. sourceSupported
• cites [35] Singhal, 2011, Targeting p53-null neuroblastomas through RLIP76, Cancer Prev. Res. sourcePartly supported

  The Results section reports that RLIP76 binds p53. The Discussion describes stress-responsive changes in RLIP76 expression, rather than directly demonstrating changes in its activity, and says HSF-1 inhibits RLIP76 without stating that the two bind. The copy provides no page numbers for these passages. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Unhealthy mitochondria emit higher levels of ROS, increasing oxidative stress and lipid peroxidation, and causing damage to mitochondrial and nuclear DNA.

“Beyond the oxidative stress generated as a byproduct of neuronal metabolism and the aberrant ROS production catalyzed by amyloid β peptide, there is also evidence that unhealthy mitochondria emit higher levels of ROS, increasing oxidative stress and lipid peroxidation, and causing damage to mitochondrial and nuclear DNA [60,61,62].”

• cites [60] Misrani, 2021, Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease, Front. Aging Neurosci. sourcePartly supported

  The ‘Oxidative Stress and Mitochondrial Defects in AD’ section (page unavailable) links impaired mitochondrial function to ROS generation and describes ROS-driven oxidative stress, lipid peroxidation, and DNA oxidation. It does not specify that both mitochondrial and nuclear DNA are damaged, so that part of the claim is more specific than the source. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [61] Abeti, 2016, Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich’s ataxia, Cell. Death Dis. sourcePartly supported

  The Results section (‘Mild mitochondrial impairment causes generation of ROS’) reports increased mitochondrial ROS, oxidative stress and lipid peroxidation in neurons from a Friedreich’s ataxia mouse model. The paper does not report that this process damages mitochondrial or nuclear DNA, and its findings are more specific than the claim’s general reference to unhealthy mitochondria. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [62] Yakes, 1997, Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress, Proc. Natl. Acad. Sci. USA sourcePartly supported

  The Discussion (page not provided) proposes that disruption of mitochondrial function could increase mitochondrial ROS and that lipid peroxidation could sustain DNA damage. The Results show damage to both mitochondrial and nuclear DNA after hydrogen peroxide exposure, but do not establish that ROS emitted by unhealthy mitochondria caused lipid peroxidation or the nuclear DNA damage. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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

Oxidative DNA damage and mitochondrial dysfunction are thought to contribute to neurodegeneration of AD, vascular dementia, HD, PD and epilepsy.

“Oxidative DNA damage and mitochondrial dysfunction are thought to contribute to the neurodegeneration of AD [75,76], vascular dementia [77], HD [78], PD [79] and epilepsy [80].”

• cites [75] Lin, X., Kapoor, A., Gu, Y., Chow, M.J., Peng, J., Zhao, K., and Tang, D. (2020). Contributions of DNA Damage to Alzheimer’s Disease. Int. J. Mol. Sci., 21. sourcePartly supported

  The cited source is attached to the AD portion of the sentence, not to the separately cited claims about vascular dementia, HD, PD, or epilepsy. Section 2, “Association of DNA Damage with Alzheimer’s Disease” (page unavailable), supports a contribution of oxidative DNA damage to AD pathogenesis. The retrieved passages do not establish the additional claim that mitochondrial dysfunction contributes to AD neurodegeneration; a reference title mentioning it is not enough. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [76] Coppede, 2009, DNA damage and repair in Alzheimer’s disease, Curr. Alzheimer Res. sourceNot checked — no full text of the source
• cites [77] Gackowski, 2008, Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia, J. Neurol. Sci. sourceNot checked — no full text of the source
• cites [78] Brocardo, 2014, The role of oxidative stress in Huntington’s disease: Are antioxidants good therapeutic candidates?, Curr. Drug. Targets sourceNot checked — no full text of the source
• cites [79] Dias, 2013, The role of oxidative stress in Parkinson’s disease, J. Parkinsons Dis. sourceSupported
• cites [80] Waldbaum, 2010, Mitochondrial dysfunction and oxidative stress: A contributing link to acquired epilepsy?, J. Bioenerg. Biomembr. sourceSupported

May combine two claims.

Brains of Alzheimer's disease patients have high levels of cerebrospinal fluid 4-HNE and increased 4-HNE adducts on neurofilaments and amyloid β plaques.

“Indeed, the brains of Alzheimer’s disease patients have high levels of cerebrospinal fluid 4-HNE and increased 4-HNE adducts on neurofilaments and amyloid β plaques [57].”

• cites [57] Dalleau, 2013, Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance, Cell. Death Differ sourcePartly supported

  The “Neurodegenerative diseases” passage in the HNE and Diseases Associated with Oxidative Damage section reports HNE adducts to neurofilaments and high HNE levels in amyloid β plaques and cerebrospinal fluid in Alzheimer’s patients. It does not say that HNE adducts on the plaques themselves are increased. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Loss of inhibitory GABAergic interneurons in hippocampus has been associated with Alzheimer's disease pathology.

“Loss of these interneurons has also been associated with Alzheimer’s disease pathology [91].”

• cites [91] Xu, 2020, GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment, Front. Neurosci. sourceSupported

May combine two claims.

Loss of function of CBP/p300 is associated with familial AD and neuronal apoptosis.

“and the loss of function of CBP/p300 is associated with familial AD and neuronal apoptosis [117,118,119,120,121].”

• cites [117] Oue, 2018, Dual functionalized liposome-mediated gene delivery across triple co-culture blood brain barrier model and specific in vivo neuronal transfection, J. Control. Release sourceCould not verify

  The Introduction discusses Alzheimer’s disease as a potential target for brain-directed gene delivery, but does not discuss CBP/p300 or familial AD. The Conclusions address neuronal transfection by liposomes, not neuronal apoptosis. Searches for CBP/p300 loss of function and related terms found no passage supporting the claimed association; the indexed passages provide no page numbers. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [118] Vieira, 2016, Getting into the brain: Liposome-based strategies for effective drug delivery across the blood-brain barrier, Int. J. Nanomed. sourceCould not verify

  The Results and discussion section discusses Alzheimer’s disease, neuronal degeneration, and liposome-based treatments, but does not address CBP/p300 loss of function or its association with familial AD and neuronal apoptosis. Searches for CBP/p300 and CREB-binding protein with those terms found no supporting passage in our copy; no page number was provided. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [119] Khan, 2013, Recent gene therapy advancements for neurological diseases, Discov. Med.Not checked yet

  Not checked in the free run.

• cites [120] Li, 2021, The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress, Nat. Aging sourcePartly supported

  The Discussion (page unavailable in our copy) says changes in CBP/p300 function are associated with Alzheimer’s disease, and the Results report that cbp-1 knockdown worsened amyloid-β aggregation in a worm AD model. Neither passage specifies familial AD or links CBP/p300 loss of function to neuronal apoptosis; the worm model expresses amyloid-β in muscle cells. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [121] Liu, 2012, Increased EID1 nuclear translocation impairs synaptic plasticity and memory function associated with pathogenesis of Alzheimer’s disease, Neurobiol. Dis. sourceSupported

May combine two claims.

Rlip+/− mice have significant reductions of synaptophysin and PSD95 in brains relative to WT, likely indicating poor synaptic health.

“We recently examined the synaptic proteins synaptophysin and PSD95 and found significant reductions of both proteins in the brains of Rlip+/− mice relative to WT mice, likely indicating poor synaptic health [14].”

• cites [14] Awasthi, S., Hindle, A., Sawant, N.A., George, M., Vijayan, M., Kshirsagar, S., Morton, H., Bunquin, L.E., Palade, P.T., and Lawrence, J.J. (2021). RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease. Cells, 10. sourcePartly supported

  Section 3.2.3 reports significant reductions in synaptophysin and PSD95 mRNA transcripts in Rlip+/− mice. Section 4.2 links reduced synaptic-gene expression to possible synaptic damage and impaired synaptic health. The passages do not establish significant reductions in the two proteins themselves, as the citing sentence says. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Activin regulates brain circuits under normal physiological conditions and is neuroprotective against acute and chronic brain damage.

“Interestingly, activin, a regulatory protein in the TGFβ family, not only regulates brain circuits under normal physiological conditions, but is also neuroprotective against acute and chronic brain damage [95].”

• cites [95] Link, 2016, Activin Signaling in the Pathogenesis and Therapy of Neuropsychiatric Diseases, Front. Mol. Neurosci. sourceSupported

May combine two claims.

4-HNE is more stable than other oxidative species, with a physiological half-life on the order of 2 min.

“Complicating matters, 4-HNE is more stable than other oxidative species, with a physiological half-life on the order of 2 min [84].”

• cites [84] Smathers, R.L., Fritz, K.S., Galligan, J.J., Shearn, C.T., Reigan, P., Marks, M.J., and Petersen, D.R. (2012). Characterization of 4-HNE modified L-FABP reveals alterations in structural and functional dynamics. PLoS ONE, 7. sourcePartly supported

  The Introduction reports a 4-HNE half-life of approximately 2 minutes and says this allows it to migrate between intracellular sites. It does not compare 4-HNE’s stability with that of other oxidative species, so the comparative part of the claim is unsupported. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

NMDA receptors are regulated by CDE and are thought to be the primary culprit in glutamate excitotoxicity, associated with brain damage in AD and ischemic brain injury.

“Providing another connection to Rlip, NMDA receptors are also regulated by CDE and are thought to be the primary culprit in glutamate excitotoxicity, a process which is associated with brain damage in Alzheimer’s disease and following ischemic brain injury [97,98].”

• cites [97] Li, 2016, Molecular mechanisms of NMDA receptor-mediated excitotoxicity: Implications for neuroprotective therapeutics for stroke, Neural Regen Res. sourcePartly supported

  The paper’s opening section links glutamate-activated NMDA receptors to excitotoxic neuronal death in Alzheimer’s disease and identifies excitotoxicity as a primary mechanism of neuronal damage in stroke. Its discussion of stroke likewise describes NMDA receptor-dependent excitotoxicity in ischemic tissue. Our copy does not say that CDE regulates NMDA receptors (searched: CDE and clathrin-mediated endocytosis). Page numbers were not provided. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [98] Cheng, 2011, alpha-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death, J. Neurochem. sourceNot checked — no full text of the source

May combine two claims.

4-HNE adducts can alter DNA base pairing, resulting in stabilized GHNE-A mispairs, which can give rise to G-C→T-A transversion mutations.

“4-HNE adducts can alter DNA base pairing, resulting in stabilized GHNE-A mispairs, which can give rise to G-C→T-A transversion mutations [82].”

• cites [82] Gentile, 2017, DNA damage by lipid peroxidation products: Implications in cancer, inflammation and autoimmunity, AIMS Genet. sourceSupported

May combine two claims.

Rlip expression is induced by oxidative stress, and Rlip serves as one of key efflux pumps for removing 4-HNE.

“Rlip expression is induced by oxidative stress, and Rlip serves as one of the key efflux pumps for removing 4-HNE [64].”

• cites [64] Cheng, 2001, Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress, J. Biol. Chem. sourceSupported

May combine two claims.

Loss of dendritic spines is a characteristic of the brains of AD patients, indicative of synaptic failure and a loss of robust neural networking.

“The loss of dendritic spines is a characteristic of the brains of AD patients, indicative of synaptic failure and a loss of robust neural networking [113].”

• cites [113] Dorostkar, 2015, Analyzing dendritic spine pathology in Alzheimer’s disease: Problems and opportunities, Acta Neuropathol. sourceSupported

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

GABA receptors are regulated by clathrin-dependent endocytosis.

“Beyond the loss of the GABAergic interneurons, GABA receptors are regulated by clathrin-dependent endocytosis [92,93].”

• cites [92] Jacob, 2008, GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition, Nat. Rev. Neurosci. sourceSupported
• cites [93] Terunuma, 2010, Functional modulation of GABAB receptors by protein kinases and receptor trafficking, Adv. Pharm. sourcePartly supported

  Section 4 states that GABAB receptors undergo constitutive clathrin-dependent endocytosis. The cited paper addresses GABAB receptors specifically, so it does not establish the claim for GABA receptors generally. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

RalA and RalB are Ras effectors which also regulate Rlip.

“RalA and RalB are Ras effectors [101] which also regulate Rlip [8,9].”

• cites [8] Dorseuil, 1995, Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity, J. Biol. Chem.Not checked yet

  Not checked in the free run.

• cites [9] Cantor, 1995, Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases, Mol. Cell. Biol. sourcePartly supported

  The ‘Binding of RalBP1 to Ral in vitro’ section shows that active Ral binds RalBP1, the protein referred to here as Rlip. But the Discussion proposes rather than demonstrates that Ral binding regulates RalBP1 activity, and the reported binding experiments do not separately establish this for RalB. The Ras-effector clause has a different citation and is not the part attributed to this paper. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [101] Kidd, 2010, Ras-related small GTPases RalA and RalB regulate cellular survival after ionizing radiation, Int. J. Radiat. Oncol. Biol. Phys. sourceSupported

May combine two claims.

Rlip is recruited to dendritic spines by activated RalA, where it interacts with the synaptic protein PSD-95.

“Additionally, Han et al. (2009) found that that Rlip is recruited to dendritic spines by activated RalA, where it interacts with the synaptic protein PSD-95 [23].”

• cites [23] Han, K., Kim, M.H., Seeburg, D., Seo, J., Verpelli, C., Han, S., Chung, H.S., Ko, J., Lee, H.W., and Kim, K. (2009). Regulated RalBP1 binding to RalA and PSD-95 controls AMPA receptor endocytosis and LTD. PLoS Biol., 7. sourceSupported

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

Dendritic spines serve as docking points for presynaptic axons.

“Dendritic spines serve as docking points for presynaptic axons, and healthy turnover of dendritic spines depends on cytoskeletal proteins [113].”

• cites [113] Dorostkar, 2015, Analyzing dendritic spine pathology in Alzheimer’s disease: Problems and opportunities, Acta Neuropathol. sourceSupported

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

Rlip is important for metastasis.

“Rlip, as might be expected for a downstream Ras effector, has been found to be important for metastasis [102].”

• cites [102] Wu, 2010, RalBP1 is necessary for metastasis of human cancer cell lines, Neoplasia sourceSupported

May combine two claims.

4-HNE decreases activity of OGG-1, resulting in increased levels of 8-hydroxydeoxyguanosine in DNA.

“Finally, 4-HNE has also been found to decrease the activity of the DNA repair enzyme 8-oxoguanine glycosylase-1 (OGG-1), possibly due to covalent alkylation of the protein, resulting in increased levels 8-hydroxydeoxyguanosine in the DNA [83].”

• cites [83] Pan, 2020, 4-Hydroxy-2-nonenal attenuates 8-oxoguanine DNA glycosylase 1 activity, J. Cell. Biochem. sourceSupported

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

Ras and Rho GTPases are important for axon and dendrite growth and guidance.

“Consistently, it has also been found that the Ras and Rho GTPases are important for axon and dendrite growth and guidance [112].”

• cites [112] Hall, 2010, Rho and Ras GTPases in axon growth, guidance, and branching, Cold Spring Harb. Perspect. Biol. sourcePartly supported

  The Abstract and “GROWING AN AXON” section describe Rho and Ras GTPases as important in axon growth and guidance. The paper mentions dendrites in its discussion of neuronal polarity, but the passages do not establish their importance for dendrite growth or guidance. No page numbers are available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Activin promotes neuroprotection by regulating balance of synaptic and extrasynaptic NMDA receptors.

“Recent evidence indicates that activin promotes neuroprotection by regulating the balance of synaptic and extrasynaptic NMDA receptors [95,96].”

• cites [95] Link, 2016, Activin Signaling in the Pathogenesis and Therapy of Neuropsychiatric Diseases, Front. Mol. Neurosci. sourceSupported
• cites [96] Lau, 2015, BDNF Reduces Toxic Extrasynaptic NMDA Receptor Signaling via Synaptic NMDA Receptors and Nuclear-Calcium-Induced Transcription of inhba/Activin, A, Cell. Rep. sourceNot checked — no full text of the source

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

Healthy turnover of dendritic spines depends on cytoskeletal proteins.

“Dendritic spines serve as docking points for presynaptic axons, and healthy turnover of dendritic spines depends on cytoskeletal proteins [113].”

• cites [113] Dorostkar, 2015, Analyzing dendritic spine pathology in Alzheimer’s disease: Problems and opportunities, Acta Neuropathol. sourceSupported

Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

Impairments in Rlip activity may cause sub-optimal responses to oxidative or genotoxic stresses, neuroinflammation, and exacerbation of neuronal damage.

“Thus, it is reasonable to hypothesize that impairments in the activity of Rlip may cause sub-optimal responses to oxidative or genotoxic stresses, neuroinflammation, and the exacerbation of neuronal damage.”

May combine two claims.

Mitochondria of Rlip+/− mice may be dysfunctional, with impaired energy production and elevated leakage of ROS into surrounding cytosol.

“Together, these results suggest that the mitochondria of Rlip+/− mice may be dysfunctional, with impaired energy production and elevated leakage of ROS into the surrounding cytosol.”

May combine two claims.

Rlip likely plays a role in mitophagy because it is an RAL effector and required for CDE, although this has not been experimentally verified.

“Because Rlip is both an RAL effector and required for CDE, it likely also plays a role in this process, although this has not been experimentally verified.”

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

Rlip is a multifunctional 76 kDa protein encoded by the RALBP1 gene on chromosome 18.

“Rlip76 (Rlip) is a multifunctional 76 kDa protein encoded by the RalA Binding Protein 1 (RALBP1) gene on chromosome 18.”

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

Rlip is evolutionarily highly conserved across species.

“Rlip is highly conserved across species [12] and is ubiquitously expressed in all tissues, including the brain [13].”

• cites [12] Fillatre, 2012, Dynamics of the subcellular localization of RalBP1/RLIP through the cell cycle: The role of targeting signals and of protein-protein interactions, FASEB J. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Rlip deficiency may contribute to reduced mitochondrial ATP production, affecting neuronal vitality and contributing to neurodegenerative diseases.

“We posit that Rlip deficiency may therefore contribute to reduced mitochondrial ATP production, perhaps affecting neuronal vitality and contributing to neurodegenerative diseases.”

May combine two claims.

Elevated 4-HNE would increase levels of total tau, p-tau, and formation of neurofibrillary tangles.

“These support a model whereby elevated 4-HNE would also increase the levels of total tau, p-tau, and consequently, increase the formation of neurofibrillary tangles.”

May combine two claims.

4-HNE-modified amyloid β peptides inhibit proteasomal function, leading to neuroinflammation which exacerbates neurodegeneration.

“4-HNE-modified amyloid β peptides have been found to inhibit proteasomal function, leading to neuroinflammation which exacerbates neurodegeneration [51,53].”

• cites [51] Rockwell, 2000, Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2), Arch. Biochem. Biophys. sourceNot checked — no full text of the source
• cites [53] Shringarpure, 2000, 4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: Possible importance in Alzheimer’s disease, Cell. Mol. Life Sci. sourceNot checked — no full text of the source

May combine two claims.

Loss of Rlip may elevate oxidative stress via both increased release of ROS and decreased detoxification of oxidative fatty acid metabolites like 4-HNE.

“Thus, loss of Rlip may elevate oxidative stress via both the increased release of ROS and decreased detoxification of oxidative fatty acid metabolites like 4-HNE.”

May combine two claims.

The Sutiman et al. result does not rule out the existence of rare variants or the possibility of effects from noncoding regions, perhaps in upstream promoters.

“This result does not rule out the existence of rare variants or the possibility of effects from noncoding regions, perhaps in upstream promoters.”

May combine two claims.

A combination of direct evidence from studies of Rlip in neurons and inferences from non-neuronal cells points toward a reasonable likelihood that disruption of Rlip functionality may impact a neuron's capacity to fine-tune its axo-dendritic connections, contributing to impoverished neural networking, neurodegeneration, and cognitive abnormalities.

“As with CDE at the presynaptic and postsynaptic terminals, a combination of direct evidence from studies of Rlip in neurons and inferences taken from the findings of studies on non-neuronal cells points toward a reasonable likelihood that disruption of Rlip functionality may impact a neuron’s capacity to fine-tune its axo-dendritic connections, contributing to impoverished neural networking, Neuro”

May combine two claims.

In 503 UK epilepsy patients genotyped for 23 common Rlip polymorphisms, 16 polymorphisms were found, of which three had a frequency of less than 1%.

“Leschziner et al. (2007) genotyped 503 UK epilepsy patients for 23 common Rlip polymorphisms. Among these patients they found 16 polymorphisms, of which three had a frequency of less than 1%.”

• cites [114] Leschziner, 2007, The association between polymorphisms in RLIP76 and drug response in epilepsy, Pharmacogenomics sourceNot checked — no full text of the source

May combine two claims.

If changes in Rlip contribute to neurodegenerative or cognitive disorders in human patients, it would likely be due to epigenetic changes in the regulation of Rlip (histone modifications or promoter methylation), altered expression of Rlip-regulating transcription factors or micro-RNAs, or possibly mutations in one of Rlip's many interaction partners, rather than coding mutations in the RALBP1基因本身

“If changes in Rlip contribute to neurodegenerative or cognitive disorders in human patients it would likely be due to epigenetic changes in the regulation of Rlip (histone modifications or promoter methylation), altered expression of Rlip-regulating transcription factors or micro-RNAs, or possibly mutations in one of Rlip’s many interaction partners, rather than coding mutations in the RALBP1 gene”

May combine two claims.

Rlip depletion in neurons would result in 4-HNE accumulation which increases DNA damage and prevents its effective repair.

“Thus, it is plausible that Rlip depletion in neurons would result in 4-HNE accumulation which not only increases DNA damage, but also prevents its effective repair.”

May combine two claims.

Sutiman et al. (2016) genotyped 100 people of Chinese descent, 100 of Malay descent, and 100 of Indian descent living in Singapore, and among the 300 subjects found no polymorphisms in exons or at exon-intron boundaries.

“By contrast, Sutiman et al. (2016) genotyped 100 people of Chinese descent, 100 of Malay descent, and 100 of Indian descent who were living in Singapore. Among the 300 subjects, the authors found no polymorphisms in exons or at exon-intron boundaries [115].”

• cites [115] Lal, 2017, Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients, Pharmacogenom. J. sourceNot checked — no full text of the source

May combine two claims.

Disruption of Rlip may have direct effects at both presynaptic and postsynaptic sides of the synaptic cleft, in addition to downstream effects from oxidative damage.

“Thus, several lines of evidence, both through direct studies involving Rlip, and through studies on CDE-dependent processes, suggest that disruption of Rlip may have direct effects at both the presynaptic and postsynaptic sides of the synaptic cleft, in addition to downstream effects arising from elevated oxidative damage.”

May combine two claims.

Rlip is a key mediator of CDE, used by neurons to balance presynaptic membrane re-uptake and regulate postsynaptic receptor densities.

“This result should not be surprising, because Rlip is a key mediator of CDE, which is used by neurons to balance presynaptic membrane re-uptake following neurotransmitter exocytosis and to regulate postsynaptic receptor densities, respectively.”

May combine two claims.

4-HNE is highly reactive and mutagenic, resulting in DNA adducts particularly on guanines.

“This is an important process because 4-HNE is highly reactive and mutagenic, resulting in DNA adducts, particularly on guanines [81], and Rlip depletion has been found to increase the accumulation of 4-HNE and its adducts.”

• cites [81] Hu, 2002, The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma, Carcinogenesis sourceNot checked — no full text of the source

May combine two claims.

The absence of exonic or exon-intron boundary Rlip polymorphisms in the 300 Asian subjects is consistent with the high degree of conservation of the RALBP1 gene between species, suggesting that Rlip protein has been highly optimized by evolution to carry out important functions, and loss of these functions by mutation results in diminished reproductive fitness and the loss of such polymorphisms.

“Such a result would be consistent with the high degree of conservation of the RALBP1 gene between species, suggesting that Rlip protein has been highly optimized by evolution to carry out important functions, and loss of these functions by mutation results in diminished reproductive fitness and the loss of such polymorphisms from the gene pool.”

• AssumptionRests on an assumption: The RALBP1 gene is highly conserved between species.

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

New axo-dendritic connections formed in this way are instrumental in learning and memory in the mature brain.

“New axo-dendritic connections formed in this way are instrumental in learning and memory in the mature brain [108].”

• cites [108] Nakajo, 2008, Genetic increase in brain-derived neurotrophic factor levels enhances learning and memory, Brain Res. sourceNot checked — no full text of the source

May combine two claims.

Rlip KO decreased seizure threshold and made mice more sensitive to the convulsant drug pentylenetetrazol.

“Bae et al. (2013) reported that Rlip KO decreased seizure threshold and made mice more sensitive to the convulsant drug pentylenetetrazol [90].”

• cites [90] Bae, 2013, Down-regulation of RalBP1 expression reduces seizure threshold and synaptic inhibition in mice, Biochem. Biophys. Res. Commun. sourceNot checked — no full text of the source