Defining a Molecular Link between Parkinson and Gaucher Diseases

定义帕金森病和戈谢病之间的分子联系

• 批准号: 8939895
• 负责人: Jennifer Lee
• 金额: $ 42.66万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939895
• 关键词: Address; Affect; Amyloid; Animal Model; Binding Proteins; Biochemical; Cell model; Ceramides; Clinical Research; Development; Disease; Energy Transfer; Enzyme Inhibition; Enzymes; Fluorescence; Gaucher Disease; Genes; Glucose; Glucosylceramides; Homeostasis; In Vitro; Investigation; Lead; Lewy Bodies; Link; Lipids; Membrane; Membrane Lipids; Minority; Molecular; Molecular Conformation; Mutation; NMR Spectroscopy; Neuronopathic Gaucher Disease; Neurons; Parkinson Disease; Pathogenesis; Pathology; Patients; Play; Proteins; Reporting; Research; Risk; Risk Factors; Role; Site; Solutions; Vesicle; Work; alpha synuclein; attenuation; disorder risk; glucosylceramidase; in vivo; insight; interest; novel therapeutics; tissue culture

Mutations in the GBA1 gene are the most common of the known risk factors for Parkinson disease (PD). While clinical studies argue a strong case towards a link between GBA1 mutations and the development of PD, mechanistic insights have been lacking. GBA1 encodes glucocerebrosidase (GCase), a lysosomal enzyme which hydrolyzes glucosylceramide (GluCer) into glucose and ceramide and is deficient in Gaucher disease (GD). Recent research suggests a relationship between GCase and the PD-related amyloid-forming protein, alpha-synuclein (alpha-syn); however, the specific molecular mechanisms responsible for association remain elusive. While the effects of GCase on alpha-syn homeostasis are the subject of considerable work, a role for alpha-synuclein in enzyme function has not been established. Such information could have further implications and indicate other mechanisms responsible for the increased PD risk. A growing number of studies show a correlation between GCase deficiency and increased alpha-syn levels, leading some to speculate that GluCer accumulation affects normal α-syn turnover. Intriguingly, we discovered a specific physical interaction exists between alpha-syn and GCase both in solution and on the lipid membrane, resulting in efficient enzyme inhibition. It is currently unresolved whether reduced GCase activity alone leads to increased alpha-syn levels. Since only a minority of GD patients and carriers develop PD, other factors are also expected to play a role in promoting pathogenesis. Obvious molecules of interest include those that modulate GCase activity and alpha-syn-GCase interaction. To address this, we have investigated whether Sap C, a vital co-factor in vivo, can affect GCase activity inhibition by alpha-syn in vitro. Remarkably, Sap C protects GCase from alpha-syn inhibition in a concentration dependent manner. Using NMR spectroscopy, site-specific fluorescence, and Frster energy transfer probes, Sap C was observed to displace alpha-syn from GCase in solution and on lipid vesicles. Taken together with the reported inverse correlation between GCase and alpha-syn levels derived from tissue culture, animal models, and patients, Sap C could act as a modifier in the homeostasis of alpha-syn. Our results might suggest different disease implications. First, the high neuronal levels of alpha-syn could lead to greater attenuation of GCase activity in patients deficient in Sap C, and this association could potentially explain why GBA1 mutations cause neuronopathic GD in some patients, but not in others. Second, if alpha-syn-GCase interaction promotes PD pathology via activity inhibition, then Sap C could play a protective role by removing alpha-syn from GCase. In this scenario, Sap C deficiency would be a risk factor for PD. Alternatively, if interaction of alpha-syn with GCase is involved in its normal lysosomal degradation as previously hypothesized, then increased Sap C levels displacing alpha-syn could potentially be harmful. Further investigation is clearly needed to determine if and to what extent Sap C and/or the interplay between Sap C, alpha-syn, and GCase is involved in PD.

GBA1 基因突变是帕金森病 (PD) 已知危险因素中最常见的。尽管临床研究有力证明 GBA1 突变与 PD 发展之间存在联系，但仍缺乏机制见解。 GBA1 编码葡萄糖脑苷脂酶 (GCase)，这是一种溶酶体酶，可将葡萄糖神经酰胺 (GluCer) 水解为葡萄糖和神经酰胺，并且在戈谢病 (GD) 中缺乏。最近的研究表明 GCase 与 PD 相关的淀粉样蛋白形成蛋白 α-突触核蛋白 (alpha-syn) 之间存在关系；然而，负责关联的具体分子机制仍然难以捉摸。虽然 GCase 对 α-syn 稳态的影响是大量工作的主题，但 α-突触核蛋白在酶功能中的作用尚未确定。此类信息可能具有进一步的影响，并表明导致局部放电风险增加的其他机制。 越来越多的研究表明 GCase 缺乏与 α-syn 水平增加之间存在相关性，导致一些人推测 GluCer 积累会影响正常的 α-syn 周转。有趣的是，我们发现溶液中和脂膜上的 α-syn 和 GCase 之间存在特定的物理相互作用，从而产生有效的酶抑制。目前尚不清楚仅减少 GCase 活性是否会导致 α-syn 水平增加。由于只有少数 GD 患者和携带者会发展为 PD，因此其他因素预计也会在促进发病过程中发挥作用。明显感兴趣的分子包括调节 GCase 活性和 α-syn-GCase 相互作用的分子。为了解决这个问题，我们研究了体内重要的辅助因子 Sap C 是否可以影响体外 α-syn 对 GCase 活性的抑制。值得注意的是，Sap C 以浓度依赖性方式保护 GCase 免受 α-syn 抑制。使用 NMR 光谱、位点特异性荧光和 Frster 能量转移探针，观察到 Sap C 可以取代溶液中和脂质囊泡上 GCase 中的 α-syn。 结合已报道的来自组织培养、动物模型和患者的 GCase 和 α-syn 水平之间的负相关性，Sap C 可以作为 α-syn 稳态的调节剂。我们的结果可能表明不同的疾病影响。首先，神经元中高水平的 α-syn 可能导致 Sap C 缺陷患者的 GCase 活性更大程度减弱，这种关联可能解释了为什么 GBA1 突变在某些患者中引起神经病性 GD，而在其他患者中则不然。其次，如果 α-syn-GCase 相互作用通过活性抑制促进 PD 病理，那么 Sap C 可以通过去除 GCase 中的 α-syn 发挥保护作用。在这种情况下，Sap C 缺乏将是 PD 的一个危险因素。或者，如果如先前假设的那样，α-syn 与 GCase 的相互作用参与其正常的溶酶体降解，那么增加 Sap C 水平取代 α-syn 可能是有害的。显然需要进一步研究以确定 Sap C 和/或 Sap C、α-syn 和 GCase 之间的相互作用是否以及在何种程度上参与 PD。