LRRK2 and RhoGTPases: Local translation in neurodegeneration

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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.