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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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294123/
https://www.ncbi.nlm.nih.gov/pubmed/35445353
http://dx.doi.org/10.1007/s13311-022-01199-7
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author 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.
author_facet 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.
author_sort Nuber, Silke
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01199-7.
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spelling pubmed-92941232022-07-20 A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity 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. Neurotherapeutics Original Article 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01199-7. Springer International Publishing 2022-04-20 2022-04 /pmc/articles/PMC9294123/ /pubmed/35445353 http://dx.doi.org/10.1007/s13311-022-01199-7 Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
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.
A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity
title A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity
title_full A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity
title_fullStr A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity
title_full_unstemmed A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity
title_short A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity
title_sort brain-penetrant stearoyl-coa desaturase inhibitor reverses α-synuclein toxicity
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294123/
https://www.ncbi.nlm.nih.gov/pubmed/35445353
http://dx.doi.org/10.1007/s13311-022-01199-7
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