miR-126 contributes to Parkinson's disease by dysregulating the insulin-like growth factor/phosphoinositide 3-kinase signaling

NEUROBIOLOGY OF AGING

卷:35

Article

Kim, Woori^1,5  Lee, Yenarae¹  McKenna, Noah D.¹  Yi, Ming²  Simunovic, Filip¹  Wang, Yulei³  Kong, Benjamin³  Rooney, Robert J.⁴  Seo, Hyemyung⁵  Stephens, Robert M.²  Sonntag, Kai C.¹ 

[1] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA 02478 USA

[2] NCI, Adv Biomed Comp Ctr, Bioinformat Support Grp, Frederick, MD 21701 USA

[3] Life Technol, Foster City, CA USA

[4] Genome Explorat Inc, Memphis, TN USA

[5] Hanyang Univ, Coll Sci & Technol, Div Mol & Life Sci, Seoul 133791, South Korea

关键词: miRNAs;    miR-126;    Dopamine neurons;    Parkinson's disease;    Insulin;    IGF-1 signaling;    PI3K;    Laser capture microdissection;    Postmortem;    6-OHDA neurotoxicity;    Cell systems;   

DOI  :  10.1016/j.neurobiolaging.2014.01.021

来源: Elsevier

【 摘 要 】

Dopamine (DA) neurons in sporadic Parkinson's disease (PD) display dysregulated gene expression networks and signaling pathways that are implicated in PD pathogenesis. Micro (mi) RNAs are regulators of gene expression, which could be involved in neurodegenerative diseases. We determined the miRNA profiles in laser microdissected DA neurons from postmortem sporadic PD patients' brains and age-matched controls. DA neurons had a distinctive miRNA signature and a set of miRNAs was dysregulated in PD. Bioinformatics analysis provided evidence for correlations of miRNAs with signaling pathways relevant to PD, including an association of miR-126 with insulin/IGF-1/PI3K signaling. In DA neuronal cell systems, enhanced expression of miR-126 impaired IGF-1 signaling and increased vulnerability to the neurotoxin 6-OHDA by downregulating factors in IGF-1/PI3K signaling, including its targets p85 beta, IRS-1, and SPRED1. Blocking of miR-126 function increased IGF-1 trophism and neuroprotection to 6-OHDA. Our data imply that elevated levels of miR-126 may play a functional role in DA neurons and in PD pathogenesis by downregulating IGF-1/PI3K/AKT signaling and that its inhibition could be a mechanism of neuroprotection. (C) 2014 Elsevier Inc. All rights reserved.

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