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.

帕金森病 (PD) 相关痴呆和路易体痴呆 (LBD) 的发病率是 在老年人口中这一比例很高，60岁以上的人中这一比例为1%，80岁以上的人中为4%。 GBA 基因是 PD 最常见的遗传风险因素之一，LBA 编码该基因。 溶酶体酶葡萄糖脑苷脂酶 (GCase) 将葡萄糖神经酰胺转化为神经酰胺 具有 GBA 突变的葡萄糖和 PD 患者发病较早，认知能力更强 GBA 突变导致帕金森病，从而导致 GCase 活性降低。 偶发性黑质和前扣带皮层的活动也显着降低 PD 和 LBD 病例，表明 GCase 活性在 PD 和 LBD 的病理生理学中发挥着关键作用。 重要的是，葡萄糖神经酰胺已被证明可以促进 α-突触核蛋白的聚集，从而导致 虽然 PD 或 LBD 无法治愈，但治疗主要是为了改善路易体的形成。 然而，包括左旋多巴和其他多巴胺激动剂在内的神经元损失。 黑质持续，多巴胺靶向治疗的有效性大大降低。 因此，确定增加 GBA 活性的机制可能是治疗的理想方法。 然而，对于那些携带突变 GBA 或 GCase 活性降低的患者进行干预。 我们最近发现 S- 调节 GBA 活动的上游机制仍然未知。 腺苷甲硫氨酸 (SAM) 合成酶 MAT2A 可能因此负向调节 GBA 活性 表明抑制 MAT2A 可能作为上调 GCase 活性的新机制 为PD和LBD提供新的治疗策略。 根据我们的初步数据，我们勇敢地面对 MAT2A 对 GBA 的负面监管 因此，针对 MAT2A 进行抑制可能会恢复 PD 和 LBD 患者的 GBA 活性 我们预计这项研究的结果将通过以下方式确定分子机制： MAT2A 控制 GBA 影响与 PD 密切相关的葡萄糖神经酰胺水平 LBD，评估响应 MAT2A 抑制而减少的葡萄糖神经酰胺是否会抑制 α- 突触核蛋白聚集和毒性，以及识别参与该途径的新候选基因 这可以作为 PD 和 LBD 的额外潜在治疗靶点。 这些研究将确定控制葡萄糖神经酰胺的上游调节机制 GBA 相关 PD 以及患有以下疾病的患者中，新陈代谢对 PD 和 LBD 的影响 在没有 GBA 突变的情况下改变 GCase 活性此外，这些研究将很好地发挥作用。 将 MAT2A 作为一种新型 PD 和 LBD 治疗策略的原理验证。