Dopamine Degradation Pathway and Alpha-synuclein Aggregation

多巴胺降解途径和 α-突触核蛋白聚集

• 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
• 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' 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' 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

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.

项目概要： 帕金森病 (PD) 的特点是中脑多巴胺能神经元逐渐丧失 黑质致密部（SNpc），导致多种显性和运动缺陷。 最近在 PD (fPD) 高患病率的家庭中发现了隐性基因突变， 约占所有 PD 病例的 15%，fPD 和散发性 PD 的一个明确病理特征是 细胞内蛋白质聚集体的存在，称为路易体 (LB)，其主要成分是蛋白质 α-突触核蛋白（α-syn）。 特性，例如通过大脑传播并在互连的大脑中触发 α-syn 聚集的能力 此外，将α-syn原纤维局部注射到野生型（WT）小鼠的大脑中会导致α-syn原纤维聚集。 这些发现表明，远离注射部位的神经元内存在α-syn。 α-syn 可以被神经元吸收并传输到互连大脑区域中的其他神经元，其中 它可以触发聚合。 尽管在支持α-syn的渐进性方面已经取得了相当大的进展 病理学方面，控制 α-syn 聚集的机制仍然知之甚少。 表明自噬和内体途径参与然而，这些一般蛋白质降解。 通路在所有细胞中普遍表达，针对这些通路可能会导致严重的副作用。 因此，确定对调节 α-syn 至关重要的多巴胺神经元特异性途径至关重要 多巴胺能神经元的一种独特作用是合成和代谢神经递质， 多巴胺的代谢产物 3,4-二羟基苯乙醛 (DOPAL) 具有高反应性。 并促进 PD 相关 α-syn 的细胞毒性聚合 我们重新认识到增强醛的作用。 脱氢酶 1a1 (ALDH1a1) – 多巴胺神经元中参与 DOPAL 氧化的关键酶 – 会减少体内α-syn的负担，从而减轻与相关的神经和行为缺陷 我们将检查 1) ALDH1a1 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 原纤维增殖；3) 过度表达或增强 ALDH1a1 功能是否有利于 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验证 最终，所提出的实验将是理解疾病治疗的重要一步。 帕金森病中 α-syn 的传播和聚集。

项目成果

Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum.

纹状体中 D2R 神经元沿背腹轴的功能和分子异质性。

• 发表时间: 2020
• 影响因子: 16.6
• 作者: Puighermanal, Emma;Castell, Laia;Esteve;Melser, Su;Kaganovsky, Konstantin;Zussy, Charleine;Boubaker;Gut, Marta;Rialle, Stephanie;Kellendonk, Christoph;Sanz, Elisenda;Quintana, Albert;Marsicano, Giovanni;Martin, Miqu
• 通讯作者: Martin, Miqu

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

多巴胺能神经元生长锥后面突触前材料的快速组装是由轴突运输的精确调节介导的。

• 发表时间: 2018
• 影响因子: 8.8
• 作者: Lipton, David M;Maeder, Celine I;Shen, Kang
• 通讯作者: Shen, Kang

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

THO 复合体协调突触发育和多巴胺神经元存活的转录。

• 发表时间: 2018
• 影响因子: 64.5
• 作者: Maeder, Celine I;Kim, Jae;Liang, Xing;Kaganovsky, Konstantin;Shen, Ao;Li, Qin;Li, Zhaoyu;Wang, Sui;Xu, X Z Shawn;Li, Jin Billy;Xiang, Yang Kevin;Ding, Jun B;Shen, Kang
• 通讯作者: Shen, Kang

The Locomotion Tug-of-War: Cholinergic and Dopaminergic Interactions Outside the Striatum.

运动拔河：纹状体外的胆碱能和多巴胺能相互作用。

• 发表时间: 2017
• 影响因子: 16.2
• 作者: Kaganovsky, Konstantin;Ding, Jun B
• 通讯作者: Ding, Jun B

Diametric neural ensemble dynamics in parkinsonian and dyskinetic states.

帕金森病和运动障碍状态下的直径神经集合动力学。

• 发表时间: 2018-05
• 影响因子: 64.8
• 作者: Parker, Jones G;Marshall, Jesse D;Ahanonu, Biafra;Wu, Yu;Kim, Tony Hyun;Grewe, Benjamin F;Zhang, Yanping;Li, Jin Zhong;Ding, Jun B;Ehlers, Michael D;Schnitzer, Mark J
• 通讯作者: Schnitzer, Mark J