SCD Inhibition Protects from α-Synuclein-Induced Neurotoxicity But Is Toxic to Early Neuron Cultures.

Here we report the independent discovery and validation of Stearoyl-CoA desaturase (SCD) as a modulator of alpha-synuclein (αSyn) induced pathology and toxicity in cell-based Parkinson’s Disease models (PD). We identified SCD as top altered gene from transcriptional profiling in primary neurons exogenously expressing αSyn with the amplified familial PD mutation 3K. Thus, we sought to further explore SCD as a therapeutic target in neurodegeneration. We report that SCD inhibitors are toxic to early human and rat neuron cultures while displaying minimal toxicity to late cultures. The fatty acid product of SCD, oleic acid, fully rescues this toxicity in early cultures, suggesting on-target toxicity. Furthermore, SCD inhibition rescues αSyn 3K induced toxicity in late primary neurons. We also confirm that SCD inhibitors reduce formation of αSyn accumulations while oleic acid increases these accumulations in an αSyn 3K neuroblastoma model. However, we identify a caveat with this model where αSyn 3K levels can be suppressed by high SCD inhibitor concentrations, obscuring true effect size. Further, we show that both SCD1 or SCD5 knockdown reduce αSyn 3K accumulations and toxicity, making both a putative drug target. Overall, we confirm key findings of published data on SCD inhibition and its benefits in αSyn accumulation and stress models. The differential neurotoxicity induced by SCD inhibition based on neuron culture age must be accounted for when researching SCD in neuron models and has potential clinical implications. Lastly, our gene profiling studies also revealed novel putative genes connected to αSyn neurotoxicity that are worth further study. Significance Statement There is no disease-modifying therapeutic for those suffering from Parkinson’s Disease (PD). Recent research has shown stearoyl-CoA desaturase (SCD) inhibition to ameliorate alpha-synuclein (αSyn) related pathology and neurotoxicity in pre-clinical PD models. The use of neuronal cell models to study PD related pathology is critical for developing putative therapeutics. In this work we demonstrate important caveats in cellular PD models when studying SCD inhibition. We also independently identified SCD and other genes as potential targets for PD. Overall, this work supports SCD as a clinical target and adds important considerations for studying SCD in in vitro models.