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)相关痴呆和路易体痴呆(LBD)发病率为 在老年人口中比例很高，60岁以上的人占1%，80岁以上的人占4%。基因突变 GBA基因是PD和LBD最常见的遗传危险因素之一。GBA对 将葡萄糖神经酰胺转化为神经酰胺的溶酶体酶葡萄糖脑苷酶(GCase)和 具有GBA突变的血糖和帕金森病患者发病更早，认知能力更强 拒绝。导致帕金森氏症的GBA突变导致GCase活性降低，GCase 散发性的黑质和前扣带回皮质的活动也显著降低。 PD和LBD病例，提示GCase活性在PD和LBD的病理生理中起关键作用。 重要的是，葡萄糖神经酰胺已被证明促进α-突触核蛋白的聚集，导致 刘易体编队。虽然PD或LBD无法治愈，但治疗主要是为了改善 症状包括L多巴等多巴胺激动剂。然而，由于脑内神经元的丢失 如果黑质持续，多巴胺靶向治疗的有效性大大降低。 因此，确定增加GBA活性的机制可能是一种理想的治疗方法 对携带突变的GBA或GCase活性降低的患者进行干预。然而， 调节GBA活性的上游机制仍不清楚。我们最近发现，S- 腺苷甲硫氨酸(SAM)合成酶MAT2A可能通过负性调节GBA活性 提示抑制MAT2A可能是上调GCase活性的一种新机制 为帕金森病和腰椎病的治疗提供了新的策略。 根据我们的初步数据，我们假设MAT2A对GBA和 因此，靶向MAT2A抑制可能会恢复PD和LBD患者的GBA活性 携带GBA突变。我们预计这项研究的结果将通过以下方式定义分子机制 哪个MAT2A控制GBA影响与PD密切相关的葡萄糖神经酰胺水平和 LBD，评估MAT2A抑制反应中还原的葡萄糖神经酰胺是否会抑制α-神经酰胺。 突触核蛋白聚集和毒性，以及确定参与这一途径的新的候选基因 可作为帕金森病和腰椎间盘突出症的潜在治疗靶点。 这些研究将确定控制葡萄糖神经酰胺的上游调控机制。 代谢在GBA相关性PD和LBD中的作用 在没有GBA突变的情况下，GCase活性发生了变化。此外，这些研究将很好地作为 靶向MAT2A作为PD和LBD治疗新策略的原则证明。