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 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–coenzyme A 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 nontransgenic mice. 5b in drinking water was given to mice expressing wild‐type 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‐ versus 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 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 α‐synucleinopathies. ANN NEUROL 2021;89:74–90

Many studies report a higher risk for Parkinson's disease (PD) and younger age of onset in men. This, and the fact that the neuropathological process underlying PD symptoms may begin before menopause, suggests that estrogen-based hormone therapy could modify this higher risk in males. However, the effects of female sex or estrogen on ␣-synuclein (␣S) homeostasis and related PD neuropathology remain unknown. Here, we used an ␣S tetramer-abrogating mouse model of PD (3K) that amplifies the familial E46K PD mutation to investigate the effects of female sex and brain-selective estrogen treatment on ␣S tetramerization and solubility, formation of vesicle-rich ␣S ϩ aggregates, dopaminergic and cortical fiber integrity, and associated motor deficits. In male 3K mice, the motor phenotype became apparent at ϳ10 weeks and increased to age 6 months, paralleled by PD-like neuropathology, whereas 3K females showed a significant delay in onset. At 6 months, this beneficial phenotypic effect in 3K females was associated with a higher ␣S tetramer-to-monomer ratio and less decrease in dopaminergic and cortical fiber length and quantity. Brain-selective estrogen treatment in symptomatic 3K mice significantly increased the tetramer-to-monomer ratio, turnover by autophagy of aggregate-prone monomers, and neurite complexity of surviving DAergic and cortical neurons, in parallel with benefits in motor performance. Our findings support an upstream role for ␣S tetramer loss in PD phenotypes and a role for estrogen in mitigating PD-like neuropathology in vivo. Brain-selective estrogen therapy may be useful in delaying or reducing PD symptoms in men and postmenopausal women.

Loss-of-function mutations in acid beta-glucosidase 1 (GBA1) are among the strongest genetic risk factors for Lewy body disorders such as Parkinson’s disease (PD) and Lewy body dementia (DLB). Altered lipid metabolism in PD patient–derived neurons, carrying either GBA1 or PD αS mutations, can shift the physiological α-synuclein (αS) tetramer–monomer (T:M) equilibrium toward aggregation-prone monomers. A resultant increase in pSer129+ αS monomers provides a likely building block for αS aggregates. 3K αS mice, representing a neuropathological amplification of the E46K PD–causing mutation, have decreased αS T:M ratios and vesicle-rich αS+ aggregates in neurons, accompanied by a striking PD-like motor syndrome. We asked whether enhancing glucocerebrosidase (GCase) expression could benefit αS dyshomeostasis by delivering an adeno-associated virus (AAV)–human wild-type (wt) GBA1 vector into the brains of 3K neonates. Intracerebroventricular AAV-wtGBA1 at postnatal day 1 resulted in prominent forebrain neuronal GCase expression, sustained through 6 mo. GBA1 attenuated behavioral deficits both in working memory and fine motor performance tasks. Furthermore, wtGBA1 increased αS solubility and the T:M ratio in both 3K-GBA mice and control littermates and reduced pS129+ and lipid-rich aggregates in 3K-GBA. We observed GCase distribution in more finely dispersed lysosomes, in which there was increased GCase activity, lysosomal cathepsin D and B maturation, decreased perilipin-stabilized lipid droplets, and a normalized TFEB translocation to the nucleus, all indicative of improved lysosomal function and lipid turnover. Therefore, a prolonged increase of the αS T:M ratio by elevating GCase activity reduced the lipid- and vesicle-rich aggregates and ameliorated PD-like phenotypes in mice, further supporting lipid modulating therapies in PD.