GTPase Activity Plays a Key Role in the Pathobiology of LRRK2

• DOI: 10.1371/journal.pgen.1000902
• Publication Date: 2010-04-08T20:04:09Z
• Authors: Yulan Xiong; Candice E. Coombes; Austin Kilaru; Xiaojie Li; Aaron D. Gitler; William J. Bowers; Valina L. Dawson; Ted M. Dawson; Darren J. Moore
• Keywords: LRRK2

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with late-onset, autosomal-dominant, familial Parkinson's disease (PD) and also contribute to sporadic disease. The LRRK2 encodes a large protein multiple domains, including functional Roc GTPase domains. most likely cause through toxic gain-of-function mechanism. expression of human variants cultured primary neurons induces toxicity that is dependent on intact GTP binding or activities. However, mechanism(s) underlying LRRK2-induced neuronal poorly understood, contribution and/or activity pathobiology not well defined. To explore LRRK2, we have developed model cytotoxicity baker's yeast Saccharomyces cerevisiae. Protein domain analysis this reveals domain-containing fragments toxic. can be modulated by altering closely defects endocytic vesicular trafficking autophagy. These truncated induce similar both models as full-length causes neurons. induced acts mechanism distinct from alpha-synuclein. A genome-wide genetic screen identified modifiers components pathways, which modulate caused variants. Our results provide insight into basic suggest may LRRK2. findings guide future therapeutic strategies aimed at attenuating LRRK2-mediated neurodegeneration.