LRRK2 and RhoGTPases: Local translation in neurodegeneration

描述（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症治疗帕金森病50多年后，我们仍然没有一种改善疾病的药物来治疗这种毁灭性的疾病，这种疾病是由黑质致密部多巴胺能神经元特异性和不可逆转的丧失引起的。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最常见的原因。虽然帕金森病的单基因原因仅占该疾病患者的一小部分，但LRRK2导致常染色体显性疾病，在病理学上与更普遍的特发性疾病难以区分。许多值得注意的研究小组描述了由G2019S氨基酸替代突变LRRK2的过度表达引起的树突和轴突缩回，最终导致神经元死亡。我们的初步研究表明，LRRK2和经典Rho GTPase之间的一种新的相互作用，Rac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的病理性突变减弱了Rho GTPases Rac和cdc42的激活，导致肌动蛋白丝的断裂，导致神经突缩回。具体来说，我们建议证明LRRK2和Rho GTPase之间存在强大的相互作用，LRRK2可以调节Rho GTPase的活性，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起的形态。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改善疗法提供新的途径。

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.