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PMID: 22171073 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning.

Human molecular genetics ·Vol. 21 ·No. 6 ·2012-03-15 ·Pages 1350-63

Dodson MW, Zhang T, Jiang C, Chen S, Guo M

Abstract

LRRK2 (PARK8) is the most common genetic determinant of Parkinson's disease (PD), with dominant mutations in LRRK2 causing inherited PD and sequence variation at the LRRK2 locus associated with increased risk for sporadic PD. Although LRRK2 has been implicated in diverse cellular processes encompassing almost all cellular compartments, the precise functions of LRRK2 remain unclear. Here, we show that the Drosophila homolog of LRRK2 (Lrrk) localizes to the membranes of late endosomes and lysosomes, physically interacts with the crucial mediator of late endosomal transport Rab7 and negatively regulates rab7-dependent perinuclear localization of lysosomes. We also show that a mutant form of lrrk analogous to the pathogenic LRRK2(G2019S) allele behaves oppositely to wild-type lrrk in that it promotes rather than inhibits rab7-dependent perinuclear lysosome clustering, with these effects of mutant lrrk on lysosome position requiring both microtubules and dynein. These data suggest that LRRK2 normally functions in Rab7-dependent lysosomal positioning, and that this function is disrupted by the most common PD-causing LRRK2 mutation, linking endolysosomal dysfunction to the pathogenesis of LRRK2-mediated PD.

MeSH Terms
Animals Animals, Genetically Modified Blotting, Western Cells, Cultured Drosophila/growth & development,metabolism Drosophila Proteins/genetics,metabolism Endosomes/metabolism Female Fertility/physiology Fluorescent Antibody Technique Immunoprecipitation Lysosomes/metabolism Male Mutation/genetics Protein Serine-Threonine Kinases/genetics,metabolism rab GTP-Binding Proteins/genetics,metabolism rab7 GTP-Binding Proteins
Chemicals
Drosophila Proteins rab7 GTP-Binding Proteins LRRK protein, Drosophila Protein Serine-Threonine Kinases rab GTP-Binding Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Dodson Mark W
Department of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Zhang Ting
Jiang Changan
Chen Shengdi
Guo Ming
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Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/ddr573
Published
2012-03-15
Epub
2011-00-13
Pages
1350-63
Language
English
Region
England
NLM ID
9208958
PMCID
PMC3284123
Subset
IM
External Links
PubMed source DOI: 10.1093/hmg/ddr573 PMC Full Text View journal details
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