title: Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration.
abstract: 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.
authors.affiliation: WCU-Neurocytomics Program, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J A
authors.initials: JA
authors.lastname: Woo
authors.forename: A R
authors.initials: AR
authors.lastname: Jung
authors.forename: M K
authors.initials: MK
authors.lastname: Lakshmana
authors.forename: A
authors.initials: A
authors.lastname: Bedrossian
authors.forename: Y
authors.initials: Y
authors.lastname: Lim
authors.forename: J H
authors.initials: JH
authors.lastname: Bu
authors.forename: S A
authors.initials: SA
authors.lastname: Park
authors.forename: E H
authors.initials: EH
authors.lastname: Koo
authors.forename: I
authors.initials: I
authors.lastname: Mook-Jung
authors.forename: D E
authors.initials: DE
authors.lastname: Kang
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction
chemical_list: D051339:Actin Depolymerizing Factors; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D003598:Cytoskeletal Proteins; D019012:Integrin beta1; D009687:Nuclear Proteins; C116005:Ran binding protein 9