2. Academic Validation
  3. Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity

Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity

  • Cell Rep. 2018 Dec 4;25(10):2742-2754.e31. doi: 10.1016/j.celrep.2018.11.028.
Benjamin M Vincent 1,  Daniel F Tardiff 2,  Jeff S Piotrowski 1,  Rebecca Aron 1,  Matthew C Lucas 1,  Chee Yeun Chung 1,  Helene Bacherman 1,  YiQun Chen 1,  Michelle Pires 1,  Radha Subramaniam 1,  Dimple B Doshi 1,  Heather Sadlish 1,  Waseem K Raja 1,  Eric J Solís 1,  Vikram Khurana 3,  Bertrand Le Bourdonnec 1,  Robert H Scannevin 1,  Kenneth J Rhodes 1
Affiliations

Affiliations

  • 1 Yumanity Therapeutics, 790 Memorial Drive, Suite 2C, Cambridge, MA 02139, USA.
  • 2 Yumanity Therapeutics, 790 Memorial Drive, Suite 2C, Cambridge, MA 02139, USA. Electronic address: dtardiff@yumanity.com.
  • 3 Yumanity Therapeutics, 790 Memorial Drive, Suite 2C, Cambridge, MA 02139, USA; Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
PMID: 30517862 DOI: 10.1016/j.celrep.2018.11.028
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.

Keywords

Parkinson’s disease; chemical genetics; fatty acid desaturation; phenotypic drug screen; stearoyl-CoA desaturase; target identification; vesicle trafficking; α-synuclein.

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