LRRK2 and RhoGTPases: Local translation in neurodegeneration

描述(申请人提供)：帕金森氏病是最常见的神经退行性运动障碍，影响近1%的65岁以上的老年人。现在，在发现并使用左旋多巴对症治疗帕金森症状50多年后，我们仍然没有一种疾病修改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。目前对帕金森氏病遗传病因的研究表明，编码富含亮氨酸重复蛋白激酶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只占这种疾病患者的一小部分，但LRRK2导致了一种常染色体显性疾病，在病理上与更普遍的特发性疾病无法区分。许多著名的研究小组描述了由G2019S氨基酸替代突变LRRK2的过度表达导致的树突和轴突回缩，最终导致神经元死亡。我们的初步研究表明，LRRK2与经典的Rho GTP酶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轴突的形态。我们假设，LRRK2的病理性突变减弱了Rho GTP酶Rac和CDC42的激活，导致肌动蛋白细丝的分解，导致轴突回缩。具体地说，我们建议证明LRRK2和Rho GTP酶之间存在强大的相互作用，LRRK2可以调节Rho GTP酶的活性，最后，由LRRK2和Rho GTP酶复合体调控的局部分子机制负责维持轴突的形态。研究LRRK2与Rho GTP酶相互作用的功能可能为帕金森病的治疗提供一条新的途径。

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.