Causes and Consequences of a-Synuclein Aggregation

α-突触核蛋白聚集的原因和后果

• 批准号: 7844885
• 负责人: ELIEZER MASLIAH
• 金额: $ 32.62万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 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/7844885
• 关键词: Ablation; Accounting; Affect; Aging; Aging-Related Process; Amyloid; Amyloid beta-Protein Precursor; Animal Model; Area; Autonomic Dysfunction; Autophagocytosis; Biochemical; Brain; Brain Stem; C-terminal; Calcium; Calcium Channel; Calpain; Caspase; Cell Line; Cells; Cleaved cell; Cognitive; Collaborations; Complex; Corpus striatum structure; Cytoskeletal Proteins; Dementia; Disease; Environment; Experimental Models; Extravasation; Funding; Generations; Genetic; Glutamate Receptor; Hippocampus (Brain); Human; Impairment; Injury; Intervention; Label; Lead; Length; Lentivirus Vector; Lewy Body Disease; Limbic System; Mediating; Membrane; Metabotropic Glutamate Receptors; Modeling; Movement Disorders; Mus; Neocortex; Neprilysin; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Oxidative Stress; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Plant Roots; Platelet-Derived Growth Factor; Population; Predisposition; Principal Investigator; Production; Proteins; Role; Seeds; Signal Pathway; Small Interfering RNA; Synapses; System; Testing; Toxic effect; Transgenic Mice; Transgenic Organisms; Viral Vector; Vulnerable Populations; alpha synuclein; caspase-3; dopaminergic neuron; familial Alzheimer disease; immunocytochemistry; in vivo; inhibitor/antagonist; metabotropic glutamate receptor 5; mutant; neurotoxic; novel; parkin gene/protein; peptide A; prevent; programs; promoter; pyridine; release of sequestered calcium ion into cytoplasm; research study; synergism

Abnormal accumulation and misfolding of a-synuclein (SYN) and amyloid-p protein (A|3) may be at the root of a wide spectrum of neurodegenerative disorders leading to dementia, parkinsonism, and autonomic dysfunction. These disorders, called Lewy body diseases, account for the great majority of cases with combined dementia and movement disorders in the U.S. Previously, we showed that A(31-42 enhances the aggregation and toxicity of SYN. In the previous funding period, we focused on the involvement of the lysosomal-endosomal pathway in the copathogenic synergism between A|31-42 and SYN. Our studies showed that A|31-42 and SYN promote neurodegeneration by interfering with autophagy and reducing the clearance of other neuronal proteins, such as parkin and cytoskeletal proteins. In this proposal, we we will test the hypothesis that A(31-42 activates calcium-dependent proteases in a glutamate receptor-dependent manner, which, in turn, results in the generation of SYN fragments that promote the formation of pathogenic SYN oligomers. We further hypothesize that this pathogenic cascade is engaged most readily in limbic and striatal neurons, which are particularly vulnerable to Lewy body diseases. To test these hypotheses, we propose the following specific aims. Aim 1: To determine if the coexpression of APP/A|3 and SYN affects the vulnerability of specific neuronal populations in the hippocampus and striatum (in collaboration with Project 5 and Cores C, D). Aim 2: To determine, in cultured neurons, if the copathogenic effects of A(3 and SYN depend on glutamate receptors and SYN cleavage (with Projects 1-3 and Cores B and D). Aim 3: To determine by genetic ablation whether the copathogenic effects of A[3 and SYN depend on the activation of a specific glutamate receptor in vivo (with Project 1). Aim 4: To determine if the impairments of transgenic mice expressing SYN and A(3 can be prevented or ameliorated by inhibiting glutamate receptors or promoting A(3 clearance (with Project 5 and Cores C and D). In collaboration with other components of the program, this project will help elucidate mechanisms of selective vulnerability and determine if interventions aimed at A|3 or A|3-dependent pathways might be useful in preventing or treating Lewy body diseases.

突触核蛋白（SYN）和淀粉样蛋白（A|（3）可能是根 广泛的神经退行性疾病导致痴呆，帕金森症和自主神经系统疾病， 功能障碍这些疾病，称为路易体病，占绝大多数情况下， 以前，我们发现A（31-42）增强了痴呆症和运动障碍。 聚集和毒性。在上一个资助期间，我们重点关注了 溶酶体-内体途径在A.| 31-42和SYN。我们的研究 表明A| 31-42和SYN通过干扰自噬和减少细胞凋亡来促进神经变性。 清除其他神经元蛋白，如parkin和细胞骨架蛋白。在这份提案中，我们将 测试假设，A（31-42）激活谷氨酸受体依赖性的钙依赖性蛋白酶， 的方式，这反过来又会导致SYN片段的产生，促进致病性 SYN低聚物。我们进一步假设，这种致病性级联反应最容易参与边缘系统， 纹状体神经元，这是特别容易受到路易体疾病。为了验证这些假设，我们 提出以下具体目标。目的1：确定APP/A的共表达是否与细胞凋亡有关，|3和SYN影响 海马和纹状体中特定神经元群体的脆弱性（与项目5合作 和核心C、D）。目的2：在体外培养的神经细胞中，观察A β和SYN的共同致病作用， 依赖于谷氨酸受体和SYN裂解（项目1-3和核心B和D）。目标3： 通过基因消融确定A[3]和SYN的共同致病作用是否依赖于A [3]的激活。 体内特异性谷氨酸受体（与项目1）。目的4：确定转基因植物的损伤是否与基因治疗有关。 表达SYN和A β的小鼠可以通过抑制谷氨酸受体或 促进A（3）级清除（与项目5和核心C和D一起）。与联合国其他部门合作， 该项目将有助于阐明选择性脆弱性的机制，并确定干预措施是否 旨在|3或|3依赖性途径可能有助于预防或治疗路易体疾病。