Dopamine Degradation Pathway and Alpha-synuclein Aggregation

多巴胺降解途径和 α-突触核蛋白聚集

基本信息

批准号：
10221065
负责人：
Jun Ding
金额：
$ 37.44万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221065
关键词：
3,4-Dihydroxyphenylacetic Acid Accounting Affect Aldehydes Alzheimer&apos s Disease Amyloid beta-Protein Amyotrophic Lateral Sclerosis Area Attenuated Autophagocytosis Behavioral Brain Brain region Carboxylic Acids Cells DNA Sequence Alteration Deamination Deep Brain Stimulation Defect Degradation Pathway Dependovirus Disease Distant Dopamine Down-Regulation Electrophysiology (science)Enzymes Exhibits Family Genetic High Prevalence Histologic Histology Human Hydrogen Peroxide In Vitro Injections Interneurons Levodopa Lewy Bodies Lysosomes Metabolic Midbrain structure Missense Mutation Molecular Monoamine Oxidase Motor Movement Movement Disorders Mus Nature Nerve Degeneration Neurodegenerative Disorders Neurons Neurotransmitters Parkinson Disease Parkinson&apos s Disease Pathway Pathologic Pathology Pathway interactions Pattern Periodicity Pharmaceutical Preparations Property Proteins Role Site Substantia nigra structure Symptoms Testing Time Transgenic Mice Up-Regulation Validation Wild Type Mouse aldehyde dehydrogenases alpha synuclein cytotoxic dopaminergic neuron experimental study in vivo insight loss of function misfolded protein mouse model neuron loss novel therapeutics overexpression oxidation pars compacta polymerization prevent prion-like protein TDP-43 protein aggregation protein degradation recessive genetic trait relating to nervous system side effect synucleinopathy tau Proteins tool transmission process

项目摘要

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.

项目摘要：帕金森氏病（PD）的特征是中脑多巴胺能神经元逐渐丧失黑质Nigra pars comcacta（SNPC），导致运动缺陷。各种主导和最近在PD患病率高（FPD）的家族中发现了隐性遗传突变，占所有PD案例的约15％。 FPD和零星PD的定义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 α-核蛋白（α-Syn）。有趣的是，最近已经假设α-Syn表现出某些“ prion样” 属性，例如能够通过大脑扩散并触发互连大脑中的α-syn聚集地区。此外，局部注射α-syn原纤维到野生型（WT）小鼠的大脑中，导致聚集远离注射部位的连接区域的神经元内的α-syn。这些发现一起表明该α-syn可以被神经元吸收，并传播到相互联系的大脑区域的其他神经元，其中它可以触发聚合。尽管已经取得了相当大的进步来支持α-syn的渐进性病理学，控制α-syn聚集的机制仍然很少了解。最近的研究建议涉及自噬和内体途径。但是，这些一般蛋白质降解途径在所有细胞中均普遍表达，靶向这些途径可能会导致严重的副作用。因此，鉴定多巴胺神经元特异性途径至关重要，这对于调节α-syn至关重要聚合。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，3,4-二羟基苯基乙醛（多帕）是高反应性的并促进与PD相关α-Syn的细胞毒性聚合。我们假设增强醛脱氢酶1A1（ALDH1A1） - 多巴胺神经元中氧化氧化的关键酶 - 会减少体内α-syn燃烧，从而减少与之相关的神经元和行为缺陷突触核酸。我们将检查1）ALDH1A1功能损失是否会增强α-Syn聚集体内2）抑制上游酶单胺氧化物（MAO）是否会降低α-syn聚集和α-syn原纤维传播； 3）过表达或提升ALDH1A1功能是否对保护多巴胺神经元免受α-syn聚集的影响。这项研究的完成将为ALDH1A1提供重要的验证，作为帕金森氏症的可行目标疾病疗法。最终，拟议的实验将是迈向理解的重要一步帕金森氏病中α-syn的传播和聚集。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival.

DOI：
10.1016/j.cell.2018.07.046
发表时间：
2018-09-06
期刊：
Cell
影响因子：
64.5
作者：
Maeder CI;Kim JI;Liang X;Kaganovsky K;Shen A;Li Q;Li Z;Wang S;Xu XZS;Li JB;Xiang YK;Ding JB;Shen K
通讯作者：
Shen K

Diametric neural ensemble dynamics in parkinsonian and dyskinetic states.

DOI：
10.1038/s41586-018-0090-6
发表时间：
2018-05
期刊：
Nature
影响因子：
64.8
作者：
Parker JG;Marshall JD;Ahanonu B;Wu YW;Kim TH;Grewe BF;Zhang Y;Li JZ;Ding JB;Ehlers MD;Schnitzer MJ
通讯作者：
Schnitzer MJ

Rapid Assembly of Presynaptic Materials behind the Growth Cone in Dopaminergic Neurons Is Mediated by Precise Regulation of Axonal Transport.