Stearoyl-CoA desaturase inhibition normalizes brain lipid saturation, α-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice

Loss-of-function mutations in the GBA1 gene are a prevalent risk factor for Parkinson's disease (PD). Defining features are Lewy bodies that can be rich in α-synuclein (αS), vesicle membranes, and other lipid membranes, coupled with striatal dopamine loss and progressive motor dysfunction. Of these, lipid abnormalities are the least understood. An altered lipid metabolism in PD patient-derived neurons - carrying mutations in either GBA1, encoding for glucocerebrosidase (GCase), or αS - shifted the physiological αS tetramer/monomer (T:M) equilibrium, resulting in PD phenotypes. We previously reported inhibition of stearoyl-CoA desaturase (SCD), the rate-limiting enzyme for fatty acid desaturation, stabilized αS tetramers and improved motor deficits in αS mice. Here we show that mutant GBA1-PD cultured neurons have increased SCD products (monounsaturated fatty acids [MUFAS]) and reduced αS T:M ratios that were improved by inhibiting SCD. Oral treatment of symptomatic L444P and E326K Gba1 mutant mice with 5b also improved the αS T:M homeostasis and dopaminergic striatal integrity. Moreover, SCD inhibition normalized GCase maturation and dampened lysosomal and lipid-rich clustering, key features of neuropathology in GBA-PD. In conclusion, this study supports that brain MUFA metabolism links GBA1 genotype and WT αS homeostasis to downstream neuronal and behavioral impairments, identifying SCD as a therapeutic target for GBA-PD.