Repression of alpha-synuclein expression and toxicity by microRNA-7.
alpha-Synuclein is a key protein in Parkinson's disease (PD) because it accumulates as fibrillar aggregates in pathologic hallmark features in affected brain regions, most notably in nigral dopaminergic neurons. Intraneuronal levels of this protein appear critical in mediating its toxicity, because multiplication of its gene locus leads to autosomal dominant PD, and transgenic animal models overexpressing human alpha-synuclein manifest impaired function or decreased survival of dopaminergic neurons. Here, we show that microRNA-7 (miR-7), which is expressed mainly in neurons, represses alpha-synuclein protein levels through the 3'-untranslated region (UTR) of alpha-synuclein mRNA. Importantly, miR-7-induced down-regulation of alpha-synuclein protects cells against oxidative stress. Further, in the MPTP-induced neurotoxin model of PD in cultured cells and in mice, miR-7 expression decreases, possibly contributing to increased alpha-synuclein expression. These findings provide a mechanism by which alpha-synuclein levels are regulated in neurons, have implications for the pathogenesis of PD, and suggest miR-7 as a therapeutic target for PD and other alpha-synucleinopathies.
Junn
Eunsung
E
Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. junneu@umdnj.edu
Lee
Kang-Woo
KW
Jeong
Byeong Seon
BS
Chan
Teresa W
TW
Im
Joo-Young
JY
Mouradian
M Maral
MM
D020413:3' Untranslated Regions / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000502:physiology*; D010300:Parkinson Disease / Q000209:etiology; D061988:Proteasome Inhibitors; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000633:toxicity
D020413:3' Untranslated Regions; D035683:MicroRNAs; D061988:Proteasome Inhibitors; D051844:alpha-Synuclein