RanBP9 at the intersection between cofilin and Aβ pathologies: rescue of neurodegenerative changes by RanBP9 reduction.
Molecular pathways underlying the neurotoxicity and production of amyloid β protein (Aβ) represent potentially promising therapeutic targets for Alzheimer's disease (AD). We recently found that overexpression of the scaffolding protein RanBP9 increases Aβ production in cell lines and in transgenic mice while promoting cofilin activation and mitochondrial dysfunction. Translocation of cofilin to mitochondria and induction of cofilin-actin pathology require the activation/dephosphorylation of cofilin by Slingshot homolog 1 (SSH1) and cysteine oxidation of cofilin. In this study, we found that endogenous RanBP9 positively regulates SSH1 levels and mediates Aβ-induced translocation of cofilin to mitochondria and induction of cofilin-actin pathology in cultured cells, primary neurons, and in vivo. Endogenous level of RanBP9 was also required for Aβ-induced collapse of growth cones in immature neurons (days in vitro 9 (DIV9)) and depletion of synaptic proteins in mature neurons (DIV21). In vivo, amyloid precursor protein (APP)/presenilin-1 (PS1) mice exhibited 3.5-fold increased RanBP9 levels, and RanBP9 reduction protected against cofilin-actin pathology, synaptic damage, gliosis, and Aβ accumulation associated with APP/PS1 mice. Brains slices derived from APP/PS1 mice showed significantly impaired long-term potentiation (LTP), and RanBP9 reduction significantly enhanced paired pulse facilitation and LTP, as well as partially rescued contextual memory deficits associated with APP/PS1 mice. Therefore, these results underscore the critical importance of endogenous RanBP9 not only in Aβ accumulation but also in mediating the neurotoxic actions of Aβ at the level of synaptic plasticity, mitochondria, and cofilin-actin pathology via control of the SSH1-cofilin pathway in vivo.
Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
J A
JA
Woo
Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
T
T
Boggess
Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
C
C
Uhlar
Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
X
X
Wang
Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
H
H
Khan
Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
G
G
Cappos
Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
A
A
Joly-Amado
Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
E
E
De Narvaez
Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
S
S
Majid
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.
L S
LS
Minamide
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.
J R
JR
Bamburg
Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
D
D
Morgan
Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
E
E
Weeber
Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
D E
DE
Kang
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; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation
D051339:Actin Depolymerizing Factors; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C116005:Ran binding protein 9