| First Author | Nuber S | Year | 2021 |
| Journal | Ann Neurol | Volume | 89 |
| Issue | 1 | Pages | 74-90 |
| PubMed ID | 32996158 | Mgi Jnum | J:301897 |
| Mgi Id | MGI:6507302 | Doi | 10.1002/ana.25920 |
| Citation | Nuber S, et al. (2021) A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in alpha-Synuclein Mice. Ann Neurol 89(1):74-90 |
| abstractText | OBJECTIVE: Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is alpha-synuclein (alphaS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing alphaS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl-coenzyme A desaturase (SCD) inhibitor ("5b") that prevented alphaS-positive vesicular inclusions and cytotoxicity in cultured human neurons. METHODS: Oral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild-type human alphaS (WT) or an amplified familial PD alphaS mutation (E35K + E46K + E61K ["3K"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD-like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD-related lipid changes were quantified in 5b- versus placebo-treated mice. Outcomes were compared to effects of crossing 3K to SCD1(-/-) mice. RESULTS: 5b treatment reduced alphaS hyperphosphorylation in E46K-expressing human neurons, in 3K neural cultures, and in both WT and 3K alphaS mice. 5b prevented subtle gait deficits in WT alphaS mice and the PD-like resting tremor and progressive motor decline of 3K alphaS mice. 5b also increased alphaS tetramers and reduced proteinase K-resistant lipid-rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation. INTERPRETATION: Prolonged reduction of brain SCD activity prevented PD-like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human alpha-synucleinopathies. ANN NEUROL 2021;89:74-90. |
