title: Mitochondrial dysfunction and calcium deregulation by the RanBP9-cofilin pathway.
abstract: Mitochondrial dysfunction and synaptic damage are important features of Alzheimer's disease (AD) associated with amyloid β (Aβ) and tau. We reported previously that the scaffolding protein RanBP9, which is overall increased in brains of patients with AD and in mutant APP transgenic mice, simultaneously promotes Aβ generation and focal adhesion disruption by accelerating the endocytosis of APP and β1-integrin, respectively. Moreover, RanBP9 induces neurodegeneration in vitro and in vivo and mediates Aβ-induced neurotoxicity. Here we show in primary hippocampal neurons that RanBP9 potentiates Aβ-induced reactive oxygen species (ROS) overproduction, apoptosis, and calcium deregulation. Analyses of calcium-handling measures demonstrate that RanBP9 selectively delays the clearance of cytosolic Ca(2+) mediated by the mitochondrial calcium uniporter through a process involving the translocation of cofilin into mitochondria and oxidative mechanisms. Further, RanBP9 retards the anterograde axonal transport of mitochondria in primary neurons and decreases synaptic mitochondrial activity in brain. These data indicate that RanBP9, cofilin, and Aβ mimic and potentiate each other to produce mitochondrial dysfunction, ROS overproduction, and calcium deregulation, which leads to neurodegenerative changes reminiscent of those seen in AD.
authors: 1Department of Molecular Medicine, USF Health Byrd Institute, 4001 E. Fletcher Ave., Tampa, FL 33613, USA. dkang@health.usf.edu.
authors: Seung-Eon
authors: SE
authors: Roh
authors: Jung A
authors: JA
authors: Woo
authors: Madepalli K
authors: MK
authors: Lakshmana
authors: Courtney
authors: C
authors: Uhlar
authors: Vinishaa
authors: V
authors: Ankala
authors: Taylor
authors: T
authors: Boggess
authors: Tian
authors: T
authors: Liu
authors: Yun-Hwa
authors: YH
authors: Hong
authors: Inhee
authors: I
authors: Mook-Jung
authors: Sang Jeong
authors: SJ
authors: Kim
authors: David E
authors: DE
authors: Kang
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001370:Axonal Transport; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; C116005:Ran binding protein 9; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C034703:mitochondrial calcium uniporter; D002118:Calcium
keywords: MTT; amyloid; axonal transport; synapse
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