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FASEB J. 2013 Dec;27(12):4776-89. doi: 10.1096/fj.13-234765. Epub 2013 Aug 27.

Mitochondrial dysfunction and calcium deregulation by the RanBP9-cofilin pathway.

Author information

1
1Department of Molecular Medicine, USF Health Byrd Institute, 4001 E. Fletcher Ave., Tampa, FL 33613, USA. dkang@health.usf.edu.

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.

KEYWORDS:

MTT; amyloid; axonal transport; synapse

PMID:
23982146
PMCID:
PMC3834781
DOI:
10.1096/fj.13-234765
[Indexed for MEDLINE]
Free PMC Article

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