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.

酸性 β-葡萄糖苷酶 1 (GBA1) 的功能丧失突变是帕金森病 (PD) 和路易体痴呆 (DLB) 等路易体疾病的最强遗传风险因素之一。携带 GBA1 或 PD αS 突变的 PD 患者衍生神经元中脂质代谢的改变可以将生理 α-突触核蛋白 (αS) 四聚体 - 单体 (T:M) 平衡转变为易于聚集的单体。由此产生的 pSer129+αS 单体增加为 αS 聚集体提供了可能的构建块。代表 E46K PD 突变的神经病理学放大的 3K αS 小鼠，神经元中的 αS T:M 比率和富含囊泡的 αS+ 聚集体降低，并伴有明显的 PD 样运动综合征。我们询问增强葡萄糖脑苷脂酶 (GCase) 表达是否可以通过将腺相关病毒 (AAV)-人类野生型 (wt) GBA1 载体递送到 3K 新生儿的大脑中来有益于 αS 稳态。出生后第 1 天的脑室内 AAV-wtGBA1 导致显着的前脑神经元 GCase 表达，持续 6 个月。GBA1 减轻了工作记忆和精细运动表现任务中的行为缺陷。此外，wtGBA1 增加了 3K-GBA 小鼠和对照同窝小鼠的 αS 溶解度和 T:M 比率，并减少了 3K-GBA 中的 pS129+ 和富含脂质的聚集体。我们观察到 GCase 在更精细分散的溶酶体中分布，其中 GCase 活性增加，溶酶体组织蛋白酶 D 和 B 成熟，perilipin 稳定的脂滴减少，以及标准化的 TFEB 易位至细胞核，所有这些都表明溶酶体功能和脂质周转得到改善。因此，通过提高 GCase 活性来延长 αS T:M 比率可减少小鼠体内富含脂质和囊泡的聚集体并改善 PD 样表型，从而进一步支持 PD 中的脂质调节疗法。