a-Synuclein (a-Syn) is a key protein in the pathogenesis of Parkinson's disease (PD) and other a- synucleinopathies. Postmortem investigations have demonstrated fibrillar a-Syn aggregates in Lewy bodies and Lewy neurites in affected brain regions in these disorders. A critical factor in the pathologic aggregation of this protein appears to be its intraneuronal concentration. Besides the fact that multiplication of the a-Syn gene locus is linked to dominantly inherited PD with an onset age that correlates inversely with gene dosage, transgenic animal models expressing wild-type human a-Syn manifest phenotypic changes reminiscent of this disease, and various cellular models in culture are made vulnerable to oxidative insults by over-expressing this protein. All these observations collectively indicate that over-expression of a-Syn is deleterious to neurons and particularly to nigral dopaminergic neurons. microRNA (miRNA) is a small (19- 24 nt) endogenous non-coding RNA which binds to the 3'-untranslational region (UTR) of mRNA in a sequence-specific manner, thereby suppressing expression of target genes. Recently, we found that miRNA-7 (miR-7) represses a-Syn protein level by targeting the 3'-UTR of this transcript. Further, miR-7- induced down-regulation of a-Syn protects cells against oxidative stress in cellular models. This application proposes to investigate the function of miRNAs including miR-7 in the pathogenesis of PD in relation to a- Syn regulation. We hypothesize that certain miRNAs repress a-Syn expression in vivo and that dysfunction of specific miRNA species results in loss of this check mechanism in disease states, leading to increased a- Syn expression and ultimately neurodegeneration. Both cellular and mouse models will be employed to carry out these investigations. Since inhibitors of a-Syn expression are attractive therapeutic targets for PD and other a-synucleinopathies, detailed understanding of these mechanisms provides potential new therapeutic approaches to slow or halt PD progression.

Public Health Relevance

Parkinson's disease and related progressive disorders of the brain have abnormal accumulation of a protein called alpha-synuclein in brain cells. The amount of this protein is critical in promoting its accumulation, which is believed to be harmful to these cells. Therefore, learning what controls the amount of this protein will help devise new treatments of these diseases. This project will study a new mechanism that controls alpha-synuclein levels.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Sutherland, Margaret L
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Rbhs-Robert Wood Johnson Medical School
Schools of Medicine
United States
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Chaudhuri, Amrita Datta; Choi, Doo Chul; Kabaria, Savan et al. (2016) MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression. J Biol Chem 291:6483-93
Kabaria, Savan; Choi, Doo Chul; Chaudhuri, Amrita Datta et al. (2015) MicroRNA-7 activates Nrf2 pathway by targeting Keap1 expression. Free Radic Biol Med 89:548-56
Chaudhuri, Amrita Datta; Kabaria, Savan; Choi, Doo Chul et al. (2015) MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium-induced Cell Death. J Biol Chem 290:12425-34
Kabaria, Savan; Choi, Doo Chul; Chaudhuri, Amrita Datta et al. (2015) Inhibition of miR-34b and miR-34c enhances α-synuclein expression in Parkinson's disease. FEBS Lett 589:319-25
Lee, Kang-Woo; Woo, Jong-Min; Im, Joo-Young et al. (2015) Apoptosis signal-regulating kinase 1 modulates the phenotype of α-synuclein transgenic mice. Neurobiol Aging 36:519-26
Grosso, Hilary; Woo, Jong-Min; Lee, Kang-Woo et al. (2014) Transglutaminase 2 exacerbates α-synuclein toxicity in mice and yeast. FASEB J 28:4280-91
Choi, Doo Chul; Chae, Yoon-Jee; Kabaria, Savan et al. (2014) MicroRNA-7 protects against 1-methyl-4-phenylpyridinium-induced cell death by targeting RelA. J Neurosci 34:12725-37
Lee, Kang-Woo; Im, Joo-Young; Woo, Jong-Min et al. (2013) Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Neurotherapeutics 10:143-53
Dias, Vera; Junn, Eunsung; Mouradian, M Maral (2013) The role of oxidative stress in Parkinson's disease. J Parkinsons Dis 3:461-91
Im, Joo-Young; Lee, Kang-Woo; Woo, Jong-Min et al. (2012) DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. Hum Mol Genet 21:3013-24

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