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

帕金森病（PD）相关痴呆和路易体痴呆（LBD）的发病率是 老年人口中的比例最高，60岁以上的占1%，80岁以上的占4%。突变 GBA基因是PD和LBD最常见的遗传危险因素之一。GBA编码了 - 溶酶体酶葡糖脑苷脂酶（GCase），其将葡糖神经酰胺转化为神经酰胺， GBA突变的PD患者发病较早， 下降GBA中的突变导致帕金森氏症导致GCase活性降低，并且GCase 活动也显着下降，在黑质和前扣带皮层在散发性 在PD和LBD病例中，表明GCase活性在PD和LBD的病理生理学中起关键作用。 重要的是，葡糖神经酰胺已显示促进α-突触核蛋白的聚集，导致 路易体形成。虽然没有治愈PD或LBD，但治疗的主要目标是改善 包括左旋多巴和其他多巴胺激动剂。然而，由于神经元的损失， 黑质继续，多巴胺靶向治疗的有效性大大降低。 因此，鉴定提高GBA活性的机制可能是治疗GBA的理想方法。 对于那些携带突变GBA或降低的GCase活性的患者进行干预。但 调控GBA活性的上游机制仍然未知。我们最近发现S- 腺苷甲硫氨酸（SAM）合成酶MAT 2A可能负调节GBA活性， 提示抑制MAT 2A可能作为上调GCase活性的新机制， 为PD和LBD提供了新的治疗策略。 基于我们的初步数据，我们假设MAT 2A负调控GBA， 因此，靶向MAT 2A进行抑制可能会恢复PD和LBD患者的GBA活性 携带GBA基因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： 其中MAT 2A控制GBA以影响与PD密切相关的葡糖神经酰胺水平， LBD，评估响应于MAT 2A抑制的葡糖神经酰胺减少是否会抑制α- 突触核蛋白聚集和毒性，以及鉴定参与该途径的新的候选基因 其可作为PD和LBD的另外的潜在治疗靶点。 这些研究将确定控制葡萄糖神经酰胺的上游调控机制 在GBA相关PD以及患有GBA相关PD的患者中， 在不存在GBA突变的情况下改变GCase活性。此外，这些研究将很好地作为 靶向MAT 2A作为新型PD和LBD治疗策略的原理验证。

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.