Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration
Open accessAbstract
Neurodegeneration associated with amyloid β (Aβ) peptide accumulation, synaptic loss, neuroinflammation, tauopathy, and memory impairments encompass the pathophysiological features of Alzheimer's disease (AD). We previously reported that the scaffolding protein RanBP9, which is overall increased in brains of AD patients, simultaneously promotes Aβ generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and β1-integrin, respectively. Here, we show that RanBP9 protein levels are increased by fourfold in FAD mutant APP transgenic mice. Accordingly, RanBP9 transgenic mice demonstrate significantly increased synapse loss, neurodegeneration, gliosis, and spatial memory deficits. RanBP9 overexpression promotes apoptosis and potentiates Aβ-induced neurotoxicity independent of its capacity to promote Aβ generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates Aβ-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both Aβ and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming Aβ generation but also antagonizing Aβ-induced neurotoxicity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
RanBP9 simultaneously promotes Aβ generation and FA disruption by accelerating APP and β1-integrin endocytosis.
“It has been also proposed that the scaffolding protein RanBP9, which exhibits an overall increase in AD brains, simultaneously promotes Aβ generation and FA disruption by accelerating APP and β1-integrin endocytosis [145].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [145]
The scaffolding protein RanBP9 exhibits an overall increase in AD brains.
“It has been also proposed that the scaffolding protein RanBP9, which exhibits an overall increase in AD brains, simultaneously promotes Aβ generation and FA disruption by accelerating APP and β1-integrin endocytosis [145].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [145]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Shankar, G. M., Bloodgood, B. L., Townsend, M., Walsh, D. M., Selkoe, D. J., & Sabatini, B. L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4970-06.2007 · Cited by 1,592 · see citing works
ADF/Cofilin: a functional node in cell biology
Bernstein, B. W., & Bamburg, J. R. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.001 · Cited by 704 · see citing works
Flagged first, then by citations
Research works printed but not linked: 24
- Bamburg JR, Bloom GS. Cytoskeletal pathologies of Alzheimer disease. Cell Motil Cytoskeleton 2009; 66: 635-649.
- Whiteman IT, Gervasio OL, Cullen KM, Guillemin GJ, Jeong EV, Witting PK et al. Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of Alzheimer-like neuritic cytoskeletal striations. J Neurosci 2009; 29: 12994-13005.
- Davis RC, Marsden IT, Maloney MT, Minamide LS, Podlisny M, Selkoe DJ et al. Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation. Mol Neurodegener 2011; 6: 10.
- Yao J, Hennessey T, Flynt A, Lai E, Beal MF, Lin MT. MicroRNA-related cofilin abnormality in Alzheimer's disease. PLoS One 2010; 5: e15546.
- Lakshmana MK, Yoon IS, Chen E, Bianchi E, Koo EH, Kang DE. Novel role of RanBP9 in BACE1 processing of amyloid precursor protein and amyloid beta peptide generation. J Biol Chem 2009; 284: 11863-11872.
- Lakshmana MK, Hayes CD, Bennett SP, Bianchi E, Reddy KM, Koo EH et al. Role of RanBP9 on amyloidogenic processing of APP and synaptic protein levels in the mouse brain. FASEB J 2012; e-pub ahead of print 31 January 2012, doi: 10.1096/fj.11-196709. · DOI
- Lakshmana MK, Chung JY, Wickramarachchi S, Tak E, Bianchi E, Koo EH et al. A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid-beta peptide generation. FASEB J 2010; 24: 119-127.
- Woo JA, Roh SE, Lakshmana MK, Kang DE. Pivotal role of RanBP9 in integrin-dependent focal adhesion signaling and assembly. FASEB J 2012; e-pub ahead of print 5 January 2012, doi: 10.1096/fj.11-194423. · DOI · Paper page
- Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000; 20: 4050-4058.
- Behl C, Widmann M, Trapp T, Holsboer F. 17-Beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun 1995; 216: 473-482.
- Klein WL. Abeta toxicity in Alzheimer's disease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int 2002; 41: 345-352.
- Wang HW, Pasternak JF, Kuo H, Ristic H, Lambert MP, Chromy B et al. Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res 2002; 924: 133-140.
- Bernard O. Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol 2007; 39: 1071-1076.
- Eiseler T, Doppler H, Yan IK, Kitatani K, Mizuno K, Storz P. Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through slingshot. Nat Cell Biol 2009; 11: 545-556.
- Klamt F, Zdanov S, Levine RL, Pariser A, Zhang Y, Zhang B et al. Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin. Nat Cell Biol 2009; 11: 1241-1246.
- Forster E, Zhao S, Frotscher M. Laminating the hippocampus. Nat Rev Neurosci 2006; 7: 259-267.
- Anderson KL, Ferreira A. Alpha1 integrin activation: a link between beta-amyloid deposition and neuronal death in aging hippocampal neurons. J Neurosci Res 2004; 75: 688-697.
- Wang Q, Klyubin I, Wright S, Griswold-Prenner I, Rowan MJ, Anwyl R. Alpha v integrins mediate beta-amyloid induced inhibition of long-term potentiation. Neurobiol Aging 2008; 29: 1485-1493.
- Chua BT, Volbracht C, Tan KO, Li R, Yu VC, Li P. Mitochondrial translocation of cofilin is an early step in apoptosis induction. Nat Cell Biol 2003; 5: 1083-1089.
- Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP et al. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci 2006; 9: 234-242.
- Ma QL, Yang F, Calon F, Ubeda OJ, Hansen JE, Weisbart RH et al. p21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis. J Biol Chem 2008; 283: 14132-14143.
- Atabakhsh E, Bryce DM, Lefebvre KJ, Schild-Poulter C. RanBPM has proapoptotic activities that regulate cell death pathways in response to DNA damage. Mol Cancer Res 2009; 7: 1962-1972.
- Kang DE, Roh SE, Woo JA, Liu T, Bu JH, Jung AR et al. The interface between cytoskeletal aberrations and mitochondrial dysfunction in Alzheimer's disease and related disorders. Exp Neurobiol 2011; 20: 67-80.
- Hotulainen P, Paunola E, Vartiainen MK, Lappalainen P. Actin-depolymerizing factor and cofilin-1 play overlapping roles in promoting rapid F-actin depolymerization in mammalian nonmuscle cells. Mol Biol Cell 2005; 16: 649-664.
Cited by
Sorted by citations
Dourlen, P., Kilinc, D., Malmanche, N., Chapuis, J., & Lambert, J.-C. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02004-0 · Cited by 168 · see citing works
More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158 · see citing works
Zaręba-Kozioł, M., Szwajda, A., Dadlez, M., Wysłouch-Cieszyńska, A., & Lalowski, M. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.036079 · Cited by 39 · see citing works
- Authors
- Woo, J. A., Jung, A. R., Lakshmana, M. K., Bedrossian, A., Lim, Y., Bu, J. H., Park, S. A., Koo, E. H., Mook-Jung, I., & Kang, D. E.
- Affiliations
- Seoul National University (KR)
- University of California San Diego (US)
- Corresponding author
- Kang, D E
- Venue
- Cell Death & Differentiation
- Published
- 2012-02-24
- Volume
- 19
- Issue
- 9
- Pages
- 1413-1423
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3422466
- OpenAlex
- W2078247521
- Cited by
- 69
- References
- 2
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 3 · 2017: 7 · 2016: 6 · 2015: 4 · 2014: 14 · 2013: 4 · 2012: 2
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Health Assistance Foundation (A2007-05)
- National Institutes of Health (7r03ag032064-03)
- National Institute on Aging (R03 AG032064, 1R03AG032064‐01, K02AG031920, R01AG033055, R01AG036859)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- RanBP9, cofilin, amyloid-beta, Alzheimer's disease, apoptosis, neurodegeneration, beta1 integrin, synaptic loss, actin dynamics, mitochondrial apoptosis, spatial memory impairment, gliosis
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cytoskeletal Proteins, Humans, Mice, Transgenic, Mitochondria, Nuclear Proteins, Phosphorylation, Signal Transduction, Amyloid beta-Peptides, Apoptosis, Integrin beta1, Adaptor Proteins, Signal Transducing, Actin Depolymerizing Factors, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
