title: miR-126 contributes to Parkinson's disease by dysregulating the insulin-like growth factor/phosphoinositide 3-kinase signaling.
abstract: 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 p85β, 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.
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA; Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: Woori
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: Yenarae
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: Noah D
authors.initials: ND
authors.lastname: McKenna
authors.affiliation: Bioinformatics Support Group, Advanced Biomedical Computing Center, NCI-Frederick, Frederick, MD, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yi
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Simunovic
authors.affiliation: Life Technologies, Foster City, CA, USA.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Life Technologies, Foster City, CA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kong
authors.affiliation: Genome Explorations Inc, Memphis, TN, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rooney
authors.affiliation: Division of Molecular & Life Sciences, College of Science & Technology, Hanyang University, Seoul, Korea.
authors.forename: Hyemyung
authors.initials: H
authors.lastname: Seo
authors.affiliation: Bioinformatics Support Group, Advanced Biomedical Computing Center, NCI-Frederick, Frederick, MD, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stephens
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA. Electronic address: ksonntag@mclean.harvard.edu.
authors.forename: Kai C
authors.initials: KC
authors.lastname: Sonntag
mesh_terms: D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D035683:MicroRNAs / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D007334:Insulin-Like Growth Factor I; D016627:Oxidopamine; D019869:Phosphatidylinositol 3-Kinases
keywords: 6-OHDA neurotoxicity; Cell systems; Dopamine neurons; IGF-1 signaling; Insulin; Laser capture microdissection; PI3K; Parkinson's disease; Postmortem; miR-126; miRNAs