Characterizing upstream regulators of glucosylceramide metabolism for Parkinson's disease and Lewy Body Dementia

帕金森病和路易体痴呆的葡萄糖神经酰胺代谢上游调节因子的特征

• 批准号: 10323690
• 负责人: Brian J. North
• 金额: $ 14.55万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323690
• 关键词: Agar; Animals; Anterior; Biological Assay; Caenorhabditis elegans; Candidate Disease Gene; Cell Culture Techniques; Ceramides; Cognitive; Data; Defect; Dementia; Dopamine; Dopamine Agonists; Effectiveness; Enzymes; Functional disorder; Gene Expression; Genes; Glucose; Glucosylceramides; Human; Impaired cognition; Incidence; Individual; Lead; Levodopa; Lewy Bodies; Lewy Body Dementia; Ligase; Link; Mammalian Cell; Measures; Metabolism; Methods; Modeling; Molecular; Movement; Mutagenesis; Mutation; Nylons; Onset of illness; Orthologous Gene; Parkinson Disease; Pathway interactions; Patients; Pharmacology; Phenotype; Proteins; Regulation; Role; S-Adenosylmethionine; SNCA gene; Substantia nigra structure; Therapeutic; Therapeutic Intervention; Toxic effect; aging population; alpha synuclein; base; cingulate cortex; early onset; forward genetics; genetic risk factor; glucosylceramidase; mutant; neuron loss; novel; response; symptomatic improvement; targeted treatment; therapeutic target; treatment strategy

Parkinson’s disease (PD)-associated dementia and Lewy Body Dementia (LBD) incidence is high among the aged population with 1% of those over 60 and 4% of those over 80. Mutations in the GBA gene represent one of the most common genetic risk factors for PD and LBD. GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) which converts glucosylceramide to ceramide and glucose, and PD patients with GBA mutations have earlier onset of disease and greater cognitive decline. Mutations in GBA leading to Parkinson’s lead to a reduction in GCase activity, and GCase activity is also significantly decreased in the substantia nigra and anterior cingulate cortex in sporadic PD and LBD cases, suggesting a critical role for GCase activity in the pathophysiology of PD and LBD. Importantly, glucosylceramide has been shown to promote aggregation of alpha-synuclein, leading to Lewy body formation. While there is no cure of PD or LBD, treatment is targeted primarily to improve symptoms, including L-DOPA and other dopamine agonists. However, as neuronal loss within the substantia nigra continues, the effectiveness of dopamine targeted therapies is greatly reduced. Therefore, identifying mechanisms to increase GBA activity may be an ideal method for therapeutic intervention for those patients harboring mutant GBA or reduced GCase activity. However, the upstream mechanisms regulating GBA activity remain unknown. We recently discovered that the S- adenosylmethionine (SAM) synthetase MAT2A may negatively regulate GBA activity thereby suggesting that inhibition of MAT2A may serve as a novel mechanism to upregulate GCase activity and provide a new treatment strategy for PD and LBD. Based on our preliminary data, we hypothesize that MAT2A negatively regulates GBA and therefore targeting MAT2A for inhibition may restore GBA activity in individuals with PD and LBD carrying mutations in GBA. We anticipate results in this study will define the molecular mechanism by which MAT2A controls GBA to influence glucosylceramide levels which are intimately linked to PD and LBD, assess whether reduced glucosylceramide in response to MAT2A inhibition will suppress alpha- synuclein aggregation and toxicity, as well as to identify new candidate genes involved in this pathway which could serve as additional potential therapeutic targets for PD and LBD. These studies will determine upstream regulatory mechanisms controlling glucosylceramide metabolism contributing to PD and LBD in both GBA-associated PD as well as patients who have altered GCase activity in the absence of GBA mutations. Furthermore, these studies will well serve as proof-of-principle for targeting MAT2A as a novel PD and LBD therapeutic strategy.

帕金森氏病（PD）相关痴呆和路易身体痴呆（LBD）发病率是 在年龄人口中，有1％以上的人口中有1％超过80％。 GBA基因代表了PD和LBD最常见的遗传危险因素之一。 GBA编码 溶酶体酶葡萄糖脑溴糖苷酶（GCASE），将葡萄糖酰亚胺转化为神经酰胺和 葡萄糖和GBA突变患者的疾病早期发作和认知较高 衰退。 GBA的突变导致帕金森的领先导致GCASE活动减少，GCASE 在零星的底质和前扣带回皮层中，活性也显着降低 PD和LBD病例，这表明GCASE活性在PD和LBD的病理生理中起关键作用。 重要的是，已显示葡萄糖基酰胺可以促进α-突触核蛋白的聚集，导致 路易的身体形成。尽管无法治愈PD或LBD，但治疗主要是针对改进的 症状，包括L-DOPA和其他多巴胺激动剂。但是，作为神经元的损失 尼格拉（Nigra）继续进行，多巴胺靶向疗法的有效性大大降低了。 因此，确定增加GBA活性的机制可能是治疗的理想方法 那些具有突变GBA或GCASE活性降低的患者的干预。但是， 调节GBA活性的上游机制尚不清楚。我们最近发现S- 腺苷硫氨酸（SAM）合成酶MAT2A可能对GBA活性负调节 表明抑制MAT2A可能是更新GCASE活动和 为PD和LBD提供新的治疗策略。 根据我们的初步数据，我们假设MAT2A负面调节GBA和 因此，针对MAT2A抑制可能会恢复PD和LBD个体的GBA活性 在GBA中携带突变。我们预计这项研究的结果将通过 MAT2A控制GBA以影响与PD密切相关的葡萄糖基酰胺水平 LBD，评估响应于MAT2A抑制作用的减少葡萄糖基酰胺是否会抑制α- 突触核蛋白的聚集和毒性，以及鉴定涉及该途径的新候选基因 可以作为PD和LBD的其他潜在治疗靶标。 这些研究将确定控制葡萄糖基酰胺的上游调节机制 在GBA相关的PD和具有的患者中，代谢有助于PD和LBD 在没有GBA突变的情况下，GCASE活动改变了。此外，这些研究将很好地作为 将MAT2A作为新型PD和LBD治疗策略的原则证明。