A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity
Abstract 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..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
Neurotherapeutics - 19(2022), 3 vom: Apr., Seite 1018-1036 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nuber, Silke [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Anmerkungen: |
© The Author(s) 2022. corrected publication 2022 |
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| doi: |
10.1007/s13311-022-01199-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Abstract 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. | ||
| 700 | 1 | |a Chung, Chee Yeun |0 (orcid)0000-0002-5515-650X |4 aut | |
| 700 | 1 | |a Tardiff, Daniel F. |4 aut | |
| 700 | 1 | |a Bechade, Pascal A. |4 aut | |
| 700 | 1 | |a McCaffery, Thomas D. |4 aut | |
| 700 | 1 | |a Shimanaka, Kazuma |4 aut | |
| 700 | 1 | |a Choi, Jeonghoon |4 aut | |
| 700 | 1 | |a Chang, Belle |4 aut | |
| 700 | 1 | |a Raja, Waseem |4 aut | |
| 700 | 1 | |a Neves, Esther |4 aut | |
| 700 | 1 | |a Burke, Christopher |4 aut | |
| 700 | 1 | |a Jiang, Xin |4 aut | |
| 700 | 1 | |a Xu, Ping |4 aut | |
| 700 | 1 | |a Khurana, Vikram |4 aut | |
| 700 | 1 | |a Dettmer, Ulf |4 aut | |
| 700 | 1 | |a Fanning, Saranna |4 aut | |
| 700 | 1 | |a Rhodes, Kenneth J. |4 aut | |
| 700 | 1 | |a Selkoe, Dennis J. |4 aut | |
| 700 | 1 | |a Scannevin, Robert H. |4 aut | |
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