LRRK2 and RhoGTPases: Local translation in neurodegeneration

LRRK2 和 RhoGTPases：神经退行性变中的局部翻译

基本信息

批准号：
8152117
负责人：
Diane Chan
金额：
$ 4.68万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-19 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8152117
关键词：
Accounting Actins Affect Affinity Amino Acid Substitution Area Attenuated Axon Binding Caspase Cell membrane Cells Cellular Stress Cessation of life Complex Cytoskeleton Dendrites Dendritic Spines Development Disease Elderly F-Actin GTP Binding Genes Genetic Immunoprecipitation Investigation Levodopa Maintenance Messenger RNA Microfilaments Molecular Morphology Motor Movement Disorders Mutation Nerve Degeneration Neurites Neurons Parkinson Disease Parkinsonian Disorders Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Play Proteins Regulation Research Role Signal Transduction Substantia nigra structure Symptoms Tertiary Protein Structure Therapeutic Time Translations axon growth dopaminergic neuron human old age (65+)immunocytochemistry inhibitor/antagonist knock-down leucine-rich repeat kinase 2 mutant neuronal cell body novel overexpression p21 activated kinase pars compacta protein complex public health relevance rac GTP-Binding Proteins rho GTP-Binding Proteins small molecule

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease is the most common neurodegenerative movement disorder affecting nearly 1% of elderly over 65 years old. Now, more than 50 years after the discovery and use of levodopa for symptomatic treatment of Parkinsonian symptoms, we still do not have a disease-modifying drug for the treatment of this devastating disease that is caused by the specific and irreversible loss of dopaminergic neurons in the substantia nigra pars compacta. Current studies on the genetic causes of Parksinson's disease reveal that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) is the most common cause of familial PD. While monogenetic causes of Parkinson's disease account for only a small percentage of the patients suffering from this disease, LRRK2 causes an autosomal-dominant disorder that is pathologically indistinguishable from the much more prevalent idiopathic disease. Many notable groups described dendritic and axonal retraction caused by the over expression of the G2019S amino-acid substitution mutation LRRK2, eventually leading to neuronal death. Our preliminary studies show that a novel interaction between LRRK2 and the classical Rho GTPase, Rac may be responsible for the maintenance of neurite morphology through the stabilization of filamentous actin. We hypothesize that pathological mutations in LRRK2 attenuates the activation of Rho GTPases Rac and cdc42 causing the disassembly of actin filaments leading to neurite retraction. Specifically, we propose to demonstrate a robust interaction between LRRK2 and Rho GTPases, that LRRK2 can regulate Rho GTPase activity and finally, that the local molecular mechanisms regulated by the LRRK2 and Rho GTPase complex is responsible for the maintenance of neurite morphology. Investigation of the function of LRRK2 interactions with Rho GTPases may serve as a novel avenue for the development of disease-modifying therapeutics for the treatment of Parkinson's disease. PUBLIC HEALTH RELEVANCE: Parkinson's disease is the most common progressive neurodegenerative movement disorder affecting nearly 1% of elderly over 65 years old. Examination of disease relevant mutations that cause Parkinson's disease may serve as a novel avenue for the development of a much needed disease-modifying therapeutic.

描述（由申请人提供）：帕金森病是最常见的神经退行性运动障碍，影响近 1% 的 65 岁以上老年人。现在，在发现并使用左旋多巴对帕金森病症状进行对症治疗 50 多年后，我们仍然没有一种疾病缓解药物来治疗这种毁灭性的疾病，这种疾病是由多巴胺能神经元的特异性和不可逆性丧失引起的。黑质致密部。目前对帕金森病遗传原因的研究表明，编码富含亮氨酸重复激酶 2 (LRRK2) 的基因突变是家族性帕金森病的最常见原因。虽然帕金森病的单基因原因只占帕金森病患者的一小部分，但 LRRK2 会引起一种常染色体显性遗传疾病，在病理学上与更常见的特发性疾病没有区别。许多著名的研究小组描述了 G2019S 氨基酸取代突变 LRRK2 的过度表达引起的树突和轴突回缩，最终导致神经元死亡。我们的初步研究表明，LRRK2 与经典 Rho GTPase、Rac 之间的新型相互作用可能通过稳定丝状肌动蛋白来维持神经突形态。我们假设 LRRK2 的病理突变减弱了 Rho GTPases Rac 和 cdc42 的激活，导致肌动蛋白丝分解，导致神经突收缩。具体来说，我们建议证明 LRRK2 和 Rho GTPase 之间的强大相互作用，即 LRRK2 可以调节 Rho GTPase 活性，最后，LRRK2 和 Rho GTPase 复合物调节的局部分子机制负责维持神经突形态。研究 LRRK2 与 Rho GTPases 相互作用的功能可能为开发治疗帕金森病的疾病缓解疗法提供新途径。公共卫生相关性：帕金森病是最常见的进行性神经退行性运动障碍，影响近 1% 的 65 岁以上老年人。检查导致帕金森病的疾病相关突变可能成为开发急需的疾病缓解疗法的新途径。