The Role of Lysosomal Glucocerebrosidase in Synucleinopathies

描述(申请人提供)：突触核病，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，其特征是α-突触核蛋白(a-syn)积聚，这是一种小的神经特异性蛋白，异常聚集成淀粉样纤维组成路易体，这是在突触核病中发现的特征性病理包裹体。帕金森病研究中的关键问题之一，以及几个神经退行性疾病研究领域的关键问题之一，是如何针对特定的有毒、致病部分进行治疗开发。控制a-syn毒性形式形成的体内过程和细胞因素在很大程度上是未知的。最近在高谢病(GD)患者中发现帕金森病和路易小体，这是一种罕见的溶酶体储存障碍，其特征是编码葡萄糖脑苷酸酶(GC)酶的基因(GBA1)突变，提示溶酶体鞘脂代谢与a-syn聚集之间存在联系。在我们的初步数据中，我们发现GCase的缺失导致了内源性α-syn的积聚，并导致了小鼠和线虫GD模型的神经变性。神经元中GCase活性受损导致GCase底物葡萄糖神经酰胺的积聚，降低溶酶体功能，并增加具有神经毒性的可溶性α-syn寡聚中间体。重要的是，我们发现α-syn的积聚能够影响神经元和人脑中溶酶体的成熟和正常GCase的活性，这表明GlcCer的积聚在散发性帕金森病和其他突触核病中也起到了作用。在这项申请中提出的实验将进一步检验GlcCer代谢变化有助于联核病发病机制的假设。我们将研究针对溶酶体的突变或正常的葡萄糖脑苷酶是否能阻止或减少毒性α-突触核蛋白低聚体的形成，并打破α-突触核蛋白聚集和毒性的恶性循环。如果成功，这些研究将进一步证实溶酶体GCase在共核病中的作用，并确定一条特定的分子途径，用于开发以a-syn积聚为特征的帕金森病和相关疾病的新疗法。 公共卫生相关性：我们建议制定策略，通过靶向在高谢病(GD)中突变的溶酶体酶葡萄糖脑苷酶来促进累积的α-α-突触核蛋白的清除。由于GD和帕金森病之间的临床和遗传联系已经建立，如果我们的方法成功，应该为帕金森病和其他突触核病的治疗开发提供一个特定的分子靶点。

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. PUBLIC HEALTH RELEVANCE: We propose to develop strategies to facilitate clearance of accumulated alpha-alpha- synuclein by targeting lysosomal enzyme glucocerebrosidase that is mutated in Gaucher disease (GD). Since clinical and genetic links between GD and parkinsonism have been established, our approach, if successful, should provide a specific molecular target for therapeutic development in parkinsonism and other synucleinopathies.