LRRK2 delays degradative receptor trafficking by impeding late endosomal budding through decreasing Rab7 activity.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset autosomal dominant Parkinson's disease (PD), and sequence variations at the LRRK2 locus are associated with increased risk for sporadic PD. LRRK2 contains both GTPase and kinase domains flanked by protein interaction motifs, and mutations associated with familial PD have ...
been described for both catalytic domains. LRRK2 has been implicated in diverse cellular processes, and recent evidence pinpoints to an important role for LRRK2 in modulating a variety of intracellular membrane trafficking pathways. However, the underlying mechanisms are poorly understood. Here, by studying the classical, well-understood, degradative trafficking pathway of the epidermal growth factor receptor (EGFR), we show that LRRK2 regulates endocytic membrane trafficking in an Rab7-dependent manner. Mutant LRRK2 expression causes a slight delay in early-to-late endosomal trafficking, and a pronounced delay in trafficking out of late endosomes, which become aberrantly elongated into tubules. This is accompanied by a delay in EGFR degradation. The LRRK2-mediated deficits in EGFR trafficking and degradation can be reverted upon coexpression of active Rab7 and of a series of proteins involved in bridging the EGFR to Rab7 on late endosomes. Effector pulldown assays indicate that pathogenic LRRK2 decreases Rab7 activity both in cells overexpressing LRRK2, as well as in fibroblasts from pathogenic mutant LRRK2 PD patients when compared with healthy controls. Together, these findings provide novel insights into a previously unknown regulation of Rab7 activity by mutant LRRK2 which impairs membrane trafficking at very late stages of the endocytic pathway.
Mesh Terms:
Brain, Case-Control Studies, Endosomes, Fibroblasts, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Parkinson Disease, Plasmids, Primary Cell Culture, Protein Structure, Tertiary, Protein Transport, Protein-Serine-Threonine Kinases, Proteolysis, Receptor, Epidermal Growth Factor, Signal Transduction, Transfection, rab GTP-Binding Proteins
Hum. Mol. Genet.
Date: Dec. 20, 2014
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