Parkinson's Disease and Mechanisms of Fast Axonal Transport

帕金森病和快速轴突运输机制

• 批准号: 7331718
• 负责人: Ramona Pufan
• 金额: $ 3.74万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331718
• 关键词: Adult; Affect; Alzheimer' s Disease; Axon; Axonal Transport; Biological; Catalytic Domain; Cell model; Cessation of life; Condition; Data; Development; Disease; Disease Progression; Disruption; Dynein ATPase; Event; Filament; Genes; Genetic; Goals; Hereditary Spastic Paraplegia; Huntington Disease; Inclusion Bodies; Kinesin; Lead; Lewy Bodies; Molecular; Molecular Conformation; Motor; Motor Neuron Disease; Mutagenesis; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organelles; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peripheral Nervous System Diseases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Post-Translational Protein Processing; Protein Isoforms; Protein Kinase C; Protein Kinase C Inhibitor; Proteins; Regulatory Pathway; Role; Site-Directed Mutagenesis; Solutions; Squid; Structure; Substantia nigra structure; Symptoms; Synapses; Testing; Work; anterograde transport; axoplasm; base; early onset; fast axonal transport; interest; kinase inhibitor; member; middle age; motor neuron degeneration; mutant; neuron loss; prevent; research study; retrograde transport; src-Family Kinases; synaptic function; synuclein; therapeutic target; trafficking

DESCRIPTION (provided by applicant): The most common adult-onset neurodegenerative motor neuron disease is Parkinson's disease (PD). Evidence supports the idea that disruption of axonal transport may cause or contribute to neurodegeneration. PD is a devastating condition that affects more than a million people in the USA alone. Current treatments ameliorate symptoms, but fail to have an effect on progression of the disease or its outcome. It is not known what causes PD, but preliminary observations indicate that pathogenic forms of alpha(a)-synuclein (mutant forms or wild type forms in Lewy body (LB) filaments) alter fast axonal transport by activating retrograde transport (RT) and reducing anterograde transport (AT). Misregulation or compromises in axonal transport have been implicated in pathogenesis of Alzheimer's and Huntington's diseases as well as motor neuron diseases such as Hereditary Spastic Paraplegia and peripheral neuropathies. We propose that the presence of mutant a-synuclein or LB disrupts proper transport in axons and thus compromises neuronal function. Disruption of fast axonal transport can be expected to result in loss of synaptic function and eventually in a loss of neurons. Our experimental aims propose to: 1) determine the role of altered kinase activity in modulating transport in cellular models of synucleinopathy. Experiments will combine pharmacological, immunochemical and molecular biological approaches to establish whether specific kinases play a role in phosphorylating the motor proteins kinesin and dynein. 2) determine molecular motifs within a-synuclein that affect kinases and axonal transport. Site directed mutagenesis of wild type and mutant a-synuclein will be carried out to identify residues and motifs critical to modulating transport. The goal is to identify potential therapeutic targets that may prevent progression of neurodegeneration in PD and protect neurons from the pathogenic consequences of mutant a-synuclein or LB. Relevance: PD is a devastating condition that has no effective treatment. Starting in middle age, patients begin neuronal degeneration that continues until death. My goal is to test possible mechanisms underlying neuronal death in PD, and to find potential therapeutic targets for this disease.

描述（由申请人提供）：最常见的成人神经退行性运动神经元疾病是帕金森氏病（PD）。证据支持这样的想法，即轴突运输的破坏可能导致或导致神经退行性。 PD是一种毁灭性的状况，仅在美国就会影响超过一百万的人。当前治疗可以缓解症状，但对疾病的进展或结果没有影响。尚不清楚是什么原因导致PD，但是初步观察表明，α（A）-Synaclein的致病形式（突变形式或Lewy体内突变形式或野生型形式（LB）丝）通过激活逆转（RT）和还原而改变快速轴突运输顺行传输（AT）。轴突运输中的正调或妥协与阿尔茨海默氏病和亨廷顿疾病的发病机理以及运动神经元疾病（如遗传性痉挛性瘫痪和周围神经病）有关。我们提出，突变A-核蛋白或LB的存在会破坏轴突中的适当转运，从而损害神经元功能。预期快速轴突转运的破坏会导致突触功能的丧失，并最终导致神经元的丧失。我们的实验目的提出：1）确定激酶活性改变在调节突触核苷模型中转运中的作用。实验将结合药理，免疫化学和分子生物学方法，以确定特定激酶是否在磷酸化运动蛋白动力素和动力蛋白中起作用。 2）确定影响激酶和轴突转运的A核蛋白内的分子基序。将进行定位的野生型诱变和突变体A-突触核蛋白的诱变，以识别对调节转运至关重要的残基和基序。目的是确定可能阻止PD神经退行性发展的潜在治疗靶标，并保护神经元免受突变A-核蛋白或LB的致病后果。相关性：PD是没有有效治疗的毁灭性疾病。从中年开始，患者开始神经元变性，一直持续到死亡。我的目标是测试PD神经元死亡的可能机制，并为该疾病找到潜在的治疗靶点。