期刊
NEUROBIOLOGY OF AGING
卷 51, 期 -, 页码 156-166出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2016.12.015
关键词
MicroRNA; Neuron; Alzheimer's disease; NOS1; S-Nitrosylation; Tau phosphorylation
资金
- Alzheimer's Association [NIRG-09-132844]
- Tau Consortium/Rainwater Foundation
MicroRNA-132 is markedly downregulated in Alzheimer's disease (AD) and related tauopathies, and its levels are closely associated with tau pathology in AD. Whether and how miR-132 contributes to pathology in these neurodegenerative diseases remains unclear. Here, we show that miR-132 and its paralogue miR-212 directly regulate the expression of neuronal nitric oxide synthase (NOS1) through the primate-specific binding site. Inhibition of miR-132 in primary human neurons and neural cells leads to increased NOS1 levels and triggers excessive production of nitric oxide, followed by aberrant S-nitrosylation (SNO) of specific proteins associated with neurodegeneration and tau pathology, such as cyclin-dependent kinase 5, dynamin-related protein 1, and glyceraldehyde-3-phosphate dehydrogenase. This, in turn, increases tau phosphorylation at disease associated Ser396, Ser404, and Ser202 sites, and impairs neural viability. Our findings indicate that downregulation of miR-132/ 212 disturbs the balance of S-nitrosylation and induces tau phosphorylation in a NOS1-dependentway, and thereby may contribute to the pathogenesis of AD and other tauopathies. (C) 2017 Elsevier Inc. All rights reserved.
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