title: Downregulation of miR-132/212 impairs S-nitrosylation balance and induces tau phosphorylation in Alzheimer's disease.
abstract: 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-dependent way, and thereby may contribute to the pathogenesis of AD and other tauopathies.
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Veremeyko
authors.affiliation: Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Andus Hon-Kit
authors.initials: AH
authors.lastname: Wong
authors.affiliation: Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Rachid
authors.initials: R
authors.lastname: El Fatimy
authors.affiliation: Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: akrichevsky@rics.bwh.harvard.edu.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Krichevsky
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009410:Nerve Degeneration / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D016875:tau Proteins; D009569:Nitric Oxide; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I
keywords: Alzheimer's disease; MicroRNA; NOS1; Neuron; S-Nitrosylation; Tau phosphorylation