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Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment.

Abstract：

:In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of αS dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased αS yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in αS-overexpressing rat neurons. In a C. elegans model, SCD knockout prevented αS-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on αS homeostasis: in human neural cells, excess OA caused αS inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for αS-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Fanning S,Haque A,Imberdis T,Baru V,Barrasa MI,Nuber S,Termine D,Ramalingam N,Ho GPH,Noble T,Sandoe J,Lou Y,Landgraf D,Freyzon Y,Newby G,Soldner F,Terry-Kantor E,Kim TE,Hofbauer HF,Becuwe M,Jaenisch R,Pincus D,

doi

10.1016/j.molcel.2018.11.028

subject

Has Abstract

pub_date

2019-03-07 00:00:00

pages

1001-1014.e8

issue

5

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(18)30998-5

journal_volume

73

pub_type

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