ROLES FOR ALPHA-SYNUCLEIN DEGRADATION AND CYTOSOLIC DOPAMINE IN PD PATHOGENESIS

α-突触核蛋白降解和胞质多巴胺在 PD 发病机制中的作用

• 批准号: 8138322
• 负责人: David Sulzer
• 金额: $ 35.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8138322
• 关键词: Acids; Animal Model; Autophagocytosis; Calcium; Carboxy-Lyases; Cell model; Cells; Cessation of life; Cultured Cells; Disease Progression; Disease model; Dopamine; Electrochemistry; Event; Genetic; Homeostasis; Impairment; Investigation; Knockout Mice; Lead; Left; Lipids; Lysosomes; Measures; Mediating; Membrane; Membrane Microdomains; Mitochondria; Modeling; Molecular Chaperones; Mono-S; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pacemakers; Parkinson Disease; Pathogenesis; Pathology; Phosphorylation; Plant Roots; Predisposition; Principal Investigator; Process; Proteins; Regulation; Reporting; Research; Role; Second Messenger Systems; Stress; Substantia nigra structure; System; Testing; Time; Ubiquitin; Ubiquitination; Up-Regulation; Ventral Tegmental Area; Work; alpha synuclein; combinatorial; design; dopaminergic neuron; inhibitor/antagonist; lysosome membrane; meetings; mouse model; multicatalytic endopeptidase complex; mutant; neuron loss; prevent; protein complex; receptor; research study; second messenger; stressor; trafficking

We will extend a line of investigation that suggests that "multiple hits", consisting of mishandling of 1) alphasynuclein (a-syn) degradation, 2) cytosolic calcium, and 3) cytosolic dopamine (DA), underlie Parkinson's disease (PD). Our preliminary results indicate that if any of these factors are absent in neuronal culture models of selective substantia nigra (SN) death, neurodegeneration can be blocked. During the prior Udall period, we 1) developed intracellular patch electrochemistry (IPE) to measure cytosolic dopamine (Mosharov et al., 2003; Mosharov et al., 2006b) and 2) reported that a-syn is specifically degraded within specialized lysosomes by chaperone-mediated autophagy (CMA), but that pathogenic a-syn mutants and DA-modified-a-syn (DA-syn) block CMA (Cuervo et al., 2004; Martinez-Vicente et al., 2008). In the current proposal, we characterize how a-syn is trafficked to lysosomes and blocks CMA (Aim 1) how cytosolic Ca++ controls cytosolic DA in SN neurons (Aim 2) and how the combination of these three "hits" disturbs normal homeostasis and may cause in pathology in mice (Aim 3).

我们将扩大一系列调查，表明“多次击中”，包括对1）α突触核蛋白的不当处理 （α-syn）降解，2）胞质钙，和3）胞质多巴胺（DA），是帕金森氏病的基础 疾病（PD）。我们的初步结果表明，如果这些因素中的任何一个在神经元培养中缺失， 选择性黑质（SN）死亡模型，神经变性可以被阻断。 在之前的Udall时期，我们1）开发了细胞内贴片电化学（IPE）来测量细胞内溶质 多巴胺（Mosarov等人，2003; Mosarov等人，2006 b）和2）报道了a-syn被特异性降解， 通过分子伴侣介导的自噬（CMA）在专门的溶酶体内，但致病性a-syn突变体 和DA-修饰的-α-syn（DA-syn）嵌段CMA（Cuervo等人，2004; Martinez-Vicente等人，2008年）。 在目前的提案中，我们描述了α-syn如何被运输到溶酶体并如何阻断CMA（Aim 1）。 胞浆Ca++控制SN神经元胞浆DA（Aim 2），以及这三种“命中”的组合如何影响SN神经元胞浆DA（Aim 2）。 扰乱正常的体内平衡，并可能导致小鼠的病理学改变（目的3）。