Cholesterol transport protein emerges as possible target for Parkinson's treatment

Parkinson's disease (PD) remains difficult to model in a lab setting, especially when searching for effective targets. However, patient-derived induced pluripotent stem cell dopaminergic neurons (iPSC-DANs) provide an encouraging solution. Calcium imbalances are well-known in PD pathophysiology, making them a suitable target for phenotypic screening.

Previous research indicated that GBA-N370S iPSC-DANs exhibit impaired calcium release. Utilizing this disease-relevant trait, a comprehensive 4,108-compound screen was conducted on GBA-N370S (GBA-NS) iPSC-DANs.

This screen pinpointed fatty acid synthase (FASN) as the most frequently targeted protein. The compounds' capacity to restore calcium release correlated with their biochemical potency against FASN across different chemical series. Knockdown of FASN enhanced intracellular calcium release, confirming a direct effect. Unanticipated lipidomics showed a wide-range alteration of the neuronal lipidome following FASN inhibition, verifying its engagement.

FASN inhibition also boosted active a-glucocerebrosidase (GCase), decreased extracellular a-synuclein release, eased ER stress, and modified RASGRF1 expression.

Mechanistically, FASN inhibition activated sterol regulatory element-binding protein 1 (SREBP1), and SREBP1 alone was sufficient to increase intracellular calcium release, recognizing a FASN-SREBP1-calcium homeostasis axis in human neurons. Lastly, the FASN inhibitor BI 99179 reached brain tissue and reduced brain fatty acid levels while triggering an SRE-associated transcriptional response in a Parkinson's mouse model, indicating in vivo target engagement.

These discoveries demonstrate that patient iPSC-neuron functional screening can be a viable discovery platform to uncover targets that can progress to in vivo testing, and the FASN-SREBP1 axis is identified as a potential therapeutic pathway for PD.