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Neuroprotective Role of microRNA-221 in DJ-1 Linked Parkinson`s disease

by
Stephanie E. Oh
B.S., Massachusetts Institute of Technology – 2009


Thesis Advisor: M. Maral Mouradian, M.D.
Graduate Program in Neuroscience

CABM, Room 010
Piscataway

Thursday, April 13, 2017
10:00 a.m.


Abstract

DJ-1 (PARK7) is a gene that is linked to recessively inherited Parkinson`s disease (PD), a progressive neurodegenerative disorder that affects over one million individuals in the US alone. A highly conserved protein that is protective in neurons and astroglia under oxidative stress conditions, DJ-1 also regulates the transcriptome by binding transcription factors and mRNA which are involved in the cell’s antioxidant response. However, non-coding RNAs modulated by DJ-1 have yet to be studied, especially microRNAs (miRNAs) which play a prominent role in the transcriptome and are recognized to have therapeutic potential in neurodegenerative diseases. We demonstrate that miR-221 expression is modulated by DJ-1 (PARK7). microRNA-221 (miR-221), one of the most abundant miRNAs in the human brain, promotes neurite outgrowth and neuronal differentiation. Yet, its role in neurological disorders has not been studied. We found that loss of DJ-1 expression results in down-regulation of miR-221 and re-introduction of wild-type DJ-1, but not its PD-linked pathogenic M26I mutant, restores miR-221 expression. Notably, miR-221 is protective against MPP+-induced cell death and is able to down-regulate the expression of several pro-apoptotic proteins at basal conditions and prevent oxidative-stress induced up-regulation of bcl-2-like protein 11 (BCL2L11/Bim/Bam). Accordingly, miR-221 protects differentiated ReNcell VM human dopaminergic neuronal cells from MPP+-induced neurite retraction and cell death. DJ-1 appears to regulate miR-221 levels, in part, through modulation of the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) pathway. These findings point to a new cytoprotective mechanism of DJ-1 through the MAPK/ERK pathway mediated by miR-221 leading to repression of apoptotic molecules. The inability of a pathogenic DJ-1 mutant to regulate miR-221 further supports the relevance of this mechanism in neuronal health and its failure in DJ-1-linked PD.


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