A stearoyl-CoA desaturase inhibitor prevents multiple Parkinson's disease-phenotypes in α-synuclein mice

Objective Parkinson's 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 α-synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl-CoA desaturase (SCD) inhibitor ("5b") that prevented αS-positive vesicular inclusions and cytotoxicity in cultured human neurons. Methods Oral dosing and brain activity of 5b were established in non-tg mice. 5b in drinking water was given to mice expressing WT human αS (WT) or an amplified familial PD αS 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- vs. placebo-treated mice. Outcomes were compared to effects of crossing 3K to SCD1-/- mice. Results 5b treatment reduced αS hyperphosphorylation in E46K-expressing human neurons, in 3K neural cultures and in both WT and 3K αS mice. 5b prevented subtle gait deficits in WT αS mice and the PD-like resting tremor and progressive motor decline of 3K αS mice. 5b also increased αS tetramers and reduced PK-resistant lipid-rich aggregates. Similar benefits accrued from genetically deleting one 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 α-synucleinopathies. This article is protected by copyright. All rights reserved.