eNeuro. 2021 Aug 7
Justin W. Nicholatos, Joost Groot, Shekhar Dhokai, David Tran, Lori Hrdlicka, Thomas M. Carlile, Melissa Bennion, Isin Dalkilic-Liddle, Warren D. Hirst, and Andreas Weihofen
Products used in the paper Details Operation
AAV vector packaging cDNAs for human aSyn, aSyn 3K (aSyn E35K 1 E46K 1 E61K) and aSyn 3K S129A were synthesized (Geneart, ThermoFisher Scientific) and subcloned into AAV entry vectors under the CAG promoter. Empty vector without insert control (EV) vectors were packaged into adeno-associated viruses (AAVs) using AAV9 capsid serotype (Packgene Biotech). Control AAV (EV) was generated using entry vector without cDNA insert. Request Quote

Research Field: CNS

Keywords: cell-based assays, lipids, neurotoxicity, Parkinson’s disease, SCD, synuclein

AAV Serotype: AAV9 capsid serotype

Targeted organ: primary cortical neuron

Animal or cell line strain: C57BL/6J mouse, Sprague Dawley female rats


Here, we report the independent discovery and validation of stearoyl-CoA desaturase (SCD) as a modulator of α-synuclein (αSyn)-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 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 (OLA), 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 OLA 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 knock-down 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.

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