Dopamine Degradation Pathway and Alpha-synuclein Aggregation

项目概要： 帕金森病（PD）的特征是中脑多巴胺能神经元的进行性丧失， 黑质神经节（SNpc），导致运动缺陷。各种各样的优势和 最近在PD（fPD）高患病率的家族中鉴定出隐性遗传突变， 占所有PD病例的约15%。fPD和散发性PD的一个定义性病理特征是 存在称为路易体（LB）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种“朊病毒样” 特性，例如在大脑中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原纤维局部注射到野生型（WT）小鼠的脑中导致α-syn原纤维的聚集。 远离注射部位的连接区域的神经元内的α-syn。总之，这些发现表明 α-syn可以被神经元吸收，并传递到相互连接的大脑区域中的其他神经元， 它可以触发聚合。 虽然在支持α-syn的渐进性方面取得了相当大的进展， 病理学上，控制α-syn聚集的机制仍然知之甚少。最近的研究 表明自噬和内体途径参与其中。然而，这些一般的蛋白质降解 由于这些通路在所有细胞中普遍表达，因此靶向这些通路可能会导致严重的副作用。 因此，确定多巴胺神经元特异性通路对调节α-syn至关重要， 聚合来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），是高度反应性的 并促进PD相关α-syn的细胞毒性聚合。我们假设， 脱氢酶1a 1（ALDH 1a 1）-多巴胺神经元中DOPAL氧化的关键酶- 将减少体内α-syn负荷，从而减轻与以下相关的神经元和行为缺陷： 共核蛋白病我们将研究1）ALDH 1a 1功能丧失是否会增强α-syn聚集， 体内; 2）抑制上游酶单胺氧化酶（MAO）是否会减少α-syn聚集 和α-syn纤维增殖; 3）是否过表达或提高ALDH 1a 1功能将有利于 保护多巴胺神经元免受α-syn聚集。 这项研究的完成将为ALDH 1a 1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 帕金森病中α-syn的传递和聚集。

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.