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Min Feng,Xin Hu,Na Li,Fan Hu,Fei Chang,Hongfei Xu,Yongjian Liu.Journal of Biomedical Research,2018,32(2):145-156
Distinctive roles of Rac1 and Rab29 in LRRK2 mediated membrane trafficking and neurite outgrowth
Received:January 30, 2017  Revised:March 03, 2017
DOI10.7555/JBR.31.20170039
KeywordsParkinson's disease, LRRK2, Rac1, Rab29, retrograde trafficking
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AuthorInstitution
Min Feng Department of Physiology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu , China.
Xin Hu Department of Physiology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu , China.
Na Li Department of Physiology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu , China.
Fan Hu Analyticaland Testing Center, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu , China.
Fei Chang Department of Physiology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu , China.
Hongfei Xu Department of Physiology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu , China.
Yongjian Liu Department of Physiology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu , China.
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Abstract
      Parkinson's disease (PD) associated leucine-rich repeat kinase 2 (LRRK2) mutants have shown pathogenic effects on a variety of subcellular processes. Two small GTPases Rac1 and Rab29 have been indicated as possible downstream effectors participating in LRRK2 signaling but their detail mechanisms remain unclear. In this study, we have used biochemical and cell biology approaches to address whether two GTPases interact with LRRK2 and hence function differently in LRRK2 mediated pathogenesis. Here we show that Rac1 and Rab29 specifically interact with LRRK2 with higher affinity for Rab29 and with different preference in functional domain binding. Mutant Rab29 but not Rac1 alters the endosome-to-TGN retrograde trafficking of a cargo protein cation-independent mannose-6- phosphate receptor (CI-M6PR) and its stability. On the other hand, overexpressed wild type Rab29 but not Rac1 rescued the altered retrograde membrane trafficking induced by the pathogenic mutant LRRK2G2019S. Furthermore, both Rac1 and Rab29 rescued neurite shortening in differentiated SH-SY5Y cells induced by LRRK2G2019S. Our study strongly suggests that Rac1 and Rab29 are involved in distinct functions as downstream effectors in LRRK2 signaling pathways.
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