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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.

Significance The mechanisms responsible for brain α-synuclein (αS) dyshomeostasis, caused by Gaucher’s GBA1 mutations that increase Parkinson’s disease (PD) risk, are largely unknown. We previously showed that abrogating physiological αS tetramers by a familial PD-E46K–amplified 3K mutation produces PD-like syndrome in mice and that treatment with stearoyl-CoA desaturase inhibitors increased a portion of the αS tetramers, benefitting the motor phenotypes. Here, we show that—similar to previous findings in GBA1-mutant PD culture—GCase elevation prolonged the stabilization of wild-type and 3K mutant αS tetramers in wtGBA1–transduced mouse brains, improving lysosomal integrity and motor and cognitive phenotypes. These data help elucidating lipid modulators that impact the αS physiological state in vivo and the development of PD therapeutic approaches., 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.

nary parenchyma or in the walls of the blood vessels. These findings, especially the plasmacytoid lymphocytes, are consistent with the pathologic diagnosis of Waldenstrom's macroglobu Iinem ia.' Shortly after the lung biopsy, the patient's hematocrit dropped from 35% to 28%, and she was also noted to have melena and guaiac-positive stools. Repeated upper gastrointestinal endoscopy was performed with the Olympus Model GFB-2 fiberscope. On this examination the body of the stomach was found to be extremely abnormal with hemorrhage, friability, adherent mucus, and nodularity. There were multiple areas of deep, irregular, poorly demarcated ulceration. The biopsy showed heavy infiltration of the stomach with lymphocytes, plasma cells and plasmacytoid lymphocytes (Figure 2). This mixed lymphoid infiltrate is consistent with Waldenstrom's disease.' The patient was treated for a month with 100 mg daily of oral cyclophosphamide, and repeated endoscopy with the Olympus Model GFB2 fiberscope revealed significant improvement. There were 3 to 4 superficial ulcerations in the distal body of the stomach. The mucosa through this area still appeared infiltrated. There was less friability of the mucosa than on the previous examination, but the endoscopic biopsy continued to show the presence of plasmacytoid lymphocytes.