Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity.

Cell Rep
Authors
Keywords
Abstract

The lack of disease-modifying treatments for neurodegenerative disease stems in part from our rudimentary understanding of disease mechanisms and the paucity of targets for therapeutic intervention. Here we used an integrated discovery paradigm to identify a new therapeutic target for diseases caused by α-synuclein (α-syn), a small lipid-binding protein that misfolds and aggregates in Parkinson's disease and other disorders. Using unbiased phenotypic screening, we identified a series of compounds that were cytoprotective against α-syn-mediated toxicity by inhibiting the highly conserved enzyme stearoyl-CoA desaturase (SCD). Critically, reducing the levels of unsaturated membrane lipids by inhibiting SCD reduced α-syn toxicity in human induced pluripotent stem cell (iPSC) neuronal models. Taken together, these findings suggest that inhibition of fatty acid desaturation has potential as a therapeutic approach for the treatment of Parkinson's disease and other synucleinopathies.

Year of Publication
2018
Journal
Cell Rep
Volume
25
Issue
10
Pages
2742-2754.e31
Date Published
2018 Dec 04
ISSN
2211-1247
DOI
10.1016/j.celrep.2018.11.028
PubMed ID
30517862
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