Dopamine Degradation Pathway and Alpha-synuclein Aggregation

项目总结： 帕金森病(PD)的特点是中脑多巴胺能神经元进行性丧失。 黑质致密部(SNPC)，导致运动缺陷。各种占主导地位的 最近在帕金森病(FPD)高发家系中发现了隐性基因突变， 约占所有帕金森病病例的15%。FPD和散发性PD的一个决定性的病理特征是 存在称为路易小体的细胞内蛋白质聚集体，其主要成分是蛋白质 α-突触核蛋白(α-syn)。有趣的是，α-syn最近被假设表现出某些类似普里恩的现象。 特性，如通过大脑传播并在相互连接的大脑中触发α-SYN聚集的能力 地区。此外，将α-SYN纤维局部注射到野生型(WT)小鼠的脑内导致聚集的 α-SYN在远离注射部位的连通区域的神经元内。总而言之，这些发现表明 这种α-SYN可以被神经元摄取并传输到相互连接的脑区的其他神经元，在那里 它可以触发聚合。 尽管在支持α-SYN的进步性方面取得了相当大的进展 病理上，控制α-SYN聚集的机制仍然知之甚少。最近的研究表明 提示自噬和内噬途径参与其中。然而，这些一般的蛋白质降解 通路在所有细胞中普遍表达，靶向这些通路可能会引起严重的副作用。 因此，识别对调节α-syn至关重要的多巴胺神经元特异性通路是至关重要的。 聚合。多巴胺能神经元的一个独特作用是合成和代谢神经递质， 多巴胺。多巴胺的代谢产物3，4-二羟基苯乙醛(DOPAL)活性很高 促进PD相关α-SYN的细胞毒聚合。我们假设增强醛 脱氢酶1a1(ALDH1A1)--多巴胺神经元氧化DOPAL的关键酶-- 会减少体内α-SYN的负荷，从而减轻与 联核症。我们将研究1)ALDH1A1功能丧失是否会增强α-SYN在 2)抑制上游单胺氧化酶(MAO)是否会减少α-SYN的聚集 和α-syn原纤维繁殖；3)过表达或提高ALDH1A1功能都有利于 保护多巴胺神经元免受α-SYN聚集。 这项研究的完成将为ALDH1A1作为帕金森病的可行靶点提供重要的验证 疾病治疗。最终，拟议中的实验将是朝着理解 α-SYN在帕金森病中的传播和聚集

Project Summary: Parkinson’s disease (PD) is characterized by a progressive loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in movement defects. A variety of dominant and recessive genetic mutations have recently been identified in families with a high prevalence of PD (fPD), accounting for ~15% of all PD cases. A defining pathological feature of both fPD and sporadic PD is the presence of intracellular protein aggregates termed Lewy bodies (LB), whose major component is the protein alpha-synuclein (α-syn). Interestingly, α-syn has recently been hypothesized to exhibit certain ‘prion-like’ properties, such as the ability to spread through the brain and trigger α-syn aggregation in interconnected brain regions. Moreover, local injection of α-syn fibrils into the brains of wild type (WT) mice leads to aggregation of α-syn within neurons of connected regions distant from the injection site. Together, these findings indicate that α-syn can be taken up by neurons and transmitted to other neurons in interconnected brain areas, where it can trigger aggregation. Although considerable progress has been made in support of the progressive nature of α-syn pathology, the mechanism controlling of α-syn aggregation remains poorly understood. Recent studies have suggested that autophagic and endosomal pathways are involved. However, these general protein degradation pathways are ubiquitously expressed in all cells, targeting these pathways may cause severe side effects. Therefore, it is critical to identify dopamine neuron specific pathway that is critical for regulating α-syn aggregation. One unique role of dopaminergic neurons is to synthesize and metabolize the neurotransmitter, dopamine. The metabolic product of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL), is highly reactive and promote cytotoxic polymerization of PD-related α-syn. We hypothesize that enhancing aldehyde dehydrogenase 1a1 (ALDH1a1) – the key enzyme involved in oxidation of DOPAL in dopamine neurons- would decrease α-syn burden in vivo thereby attenuating neuronal and behavioral defects associated with synucleinopathy. We will examine 1) whether ALDH1a1 loss of function would enhance α-syn aggregation in vivo; 2) whether inhibiting upstream enzyme monoamine oxidase (MAO) would decrease α-syn aggregation and α-syn fibril propagation; 3) whether overexpression or elevate ALDH1a1 function would be beneficial to protect dopamine neuron against α-syn aggregation. Completion of this study will provide important validation of ALDH1a1 as a viable target for Parkinson’s disease therapy. Ultimately, the proposed experiments will be a major step towards the understanding of transmission and aggregation of α-syn in Parkinson’s disease.