A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity

Increasing evidence has shown that Parkinson’s disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential...

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Bibliographic Details
Published in:Neurotherapeutics 2022-04, Vol.19 (3), p.1018-1036
Main Authors: Nuber, Silke, Chung, Chee Yeun, Tardiff, Daniel F., Bechade, Pascal A., McCaffery, Thomas D., Shimanaka, Kazuma, Choi, Jeonghoon, Chang, Belle, Raja, Waseem, Neves, Esther, Burke, Christopher, Jiang, Xin, Xu, Ping, Khurana, Vikram, Dettmer, Ulf, Fanning, Saranna, Rhodes, Kenneth J., Selkoe, Dennis J., Scannevin, Robert H.
Format: Article
Language:English
Subjects:
alpha-Synuclein - genetics
alpha-Synuclein - metabolism
Animals
Biomedical and Life Sciences
Biomedicine
Blood-brain barrier
Brain - metabolism
Cell culture
Clinical trials
Cytotoxicity
Desaturase
Dopamine receptors
Fatty acids
Gene deletion
Humans
Mesencephalon
Mice
Movement disorders
Neurobiology
Neurodegenerative diseases
Neurology
Neurons - metabolism
Neurosciences
Neurospheres
Neurosurgery
Neurotoxicity
Original
Original Article
Parkinson Disease - genetics
Parkinson's disease
Phenotypes
Scd1 protein
Stearoyl-CoA desaturase
Stearoyl-CoA Desaturase - genetics
Stearoyl-CoA Desaturase - metabolism
Synuclein
Therapeutic applications
Therapeutic targets
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Summary:Increasing evidence has shown that Parkinson’s disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential therapeutic target for synucleinopathies. A brain-penetrant SCD inhibitor, YTX-7739, was developed and has entered Phase 1 clinical trials. Here, we report the efficacy of YTX-7739 in reversing pathological αSyn phenotypes in various in vitro and in vivo PD models. In cell-based assays, YTX-7739 decreased αSyn-mediated neuronal death, reversed the abnormal membrane interaction of amplified E46K (“3K”) αSyn, and prevented pathological phenotypes in A53T and αSyn triplication patient-derived neurospheres, including dysregulated fatty acid profiles and pS129 αSyn accumulation. In 3K PD-like mice, YTX-7739 crossed the blood–brain barrier, decreased unsaturated fatty acids, and prevented progressive motor deficits. Both YTX-7739 treatment and decreasing SCD activity through deletion of one copy of the SCD1 gene (SKO) restored the physiological αSyn tetramer-to-monomer ratio, dopaminergic integrity, and neuronal survival in 3K αSyn mice. YTX-7739 efficiently reduced pS129 + and PK-resistant αSyn in both human wild-type αSyn and 3K mutant mice similar to the level of 3K-SKO. Together, these data provide further validation of SCD as a PD therapeutic target and YTX-7739 as a clinical candidate for treating human α-synucleinopathies.
ISSN:1933-7213
1878-7479
1878-7479
DOI:10.1007/s13311-022-01199-7