SCD Inhibition Protects from alpha-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 (alpha Syn)- induced pathology and toxicity in cell-based Parkinson's disease (PD) models. We identified SCD as top altered gene from transcriptional profiling in primary neurons exogenously expressing alpha Syn 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 (OLA), fully rescues this toxicity in early cultures, suggesting on-target toxicity. Furthermore, SCD inhibition rescues alpha Syn 3K-induced toxicity in late primary neurons. We also confirm that SCD inhibitors reduce formation of alpha Syn accumulations, while OLA increases these accumulations in an alpha Syn 3K neuroblastoma model. However, we identify a caveat with this model where alpha Syn 3K levels can be suppressed by high SCD inhibitor concentrations, obscuring true effect size. Further, we show that both SCD1 or SCD5 knock-down reduce alpha Syn 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 alpha Syn 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 alpha Syn neurotoxicity that are worth further study.