The Role of Lysosomal Glucocerebrosidase in Synucleinopathies

描述（由申请人提供）：突触核蛋白病，包括路易体痴呆（DLB）、多系统萎缩（MSA）和帕金森病（PD），是一组神经退行性疾病，其特征在于α-突触核蛋白（α-syn）的积累，α-syn是一种小的神经特异性蛋白，异常聚集成包含路易体的淀粉样原纤维，是突触核蛋白病中发现的特征性病理性包涵体。PD研究以及几个神经退行性疾病研究领域的关键问题之一是如何靶向特定的毒性，致病性部分用于治疗开发。控制α-syn毒性形式形成的体内过程和细胞因子在很大程度上是未知的。最近在戈谢病（GD）患者中发现帕金森综合征和路易体，戈谢病是一种罕见的溶酶体贮积症，其特征在于编码葡萄糖脑苷脂酶（GC）的基因（GBA 1）突变，这表明溶酶体鞘脂代谢和α-syn聚集之间存在联系。在我们的初步数据中，我们表明GCase的缺失导致小鼠和C. elegans GD模型。神经元中受损的GCase活性导致GCase底物葡糖神经酰胺的积累，溶酶体功能减弱，并增加具有神经毒性的可溶性α-syn寡聚体中间体。重要的是，我们发现α-syn积累能够影响神经元和人脑中正常GCase的溶酶体成熟和活性，表明GlcCer积累也在散发性PD和其他突触核蛋白病中起作用。本申请中提出的实验将进一步检验GlcCer代谢的改变有助于突触核蛋白病的发病机制的假设。我们将检查突变的或正常的葡萄糖脑苷脂酶治疗性靶向溶酶体是否防止或减少毒性α-突触核蛋白寡聚体的形成并打破α-突触核蛋白聚集和毒性的恶性循环。如果成功，这些研究将进一步验证溶酶体GCase在突触核蛋白病中的作用，并确定用于开发PD和以α-syn积累为特征的相关疾病的新疗法的特定分子途径。

DESCRIPTION (provided by applicant): The synucleinopathies, including Dementia with Lewy bodies (DLB), Multiple system atrophy (MSA), and Parkinson's disease (PD), are a group of neurodegenerative disorders characterized by the accumulation of alpha-synuclein (a-syn), a small neural- specific protein that aberrantly aggregates into amyloid fibrils that comprise Lewy bodies, the characteristic pathological inclusions found in synucleinopathies. One of the critical issues in PD research, as well as across several neurodegenerative disease research areas, is how to target the specific toxic, pathogenic moiety for therapeutic development. The in vivo processes and cellular factors that control the formation of a-syn toxic forms are largely unknown. The recent discovery of parkinsonism and Lewy bodies in patients with Gaucher disease (GD), a rare lysosomal storage disorder characterized by mutations in the gene (GBA1) encoding glucocerebrosidase (GC)ase, suggests a link between lysosomal sphingolipid metabolism and a-syn aggregation. In our preliminary data we show that depletion of GCase results in endogenous a-syn accumulation and neurodegeneration in mouse and C. elegans models of GD. Compromised GCase activity in neurons led to accumulation of the GCase substrate glucosylceramide, diminished lysosomal function, and increased soluble a-syn oligomeric intermediates that were neurotoxic. Importantly, we found that a-syn accumulation has the ability to affect the lysosomal maturation and activity of normal GCase in neurons and human brain, suggesting that GlcCer accumulation also plays a role in sporadic PD and other synucleinopathies. The experiments proposed in this application will further test the hypothesis that alterations in GlcCer metabolism contribute to the pathogenesis of synucleinopathies. We will examine whether therapeutic targeting of mutated or normal glucocerebrosidase to lysosomes prevents or diminishes formation of toxic alpha- synuclein oligomers and breaks the vicious cycle of alpha-synuclein aggregation and toxicity. If successful, these studies will provide further validation for a role of lysosomal GCase in synucleinopathies and identify a specific molecular pathway for the development of new therapies for PD and related diseases characterized by accumulation of a-syn.