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Hum Mol Genet. 2014 Dec 20;23(25):6779-96. doi: 10.1093/hmg/ddu395. Epub 2014 Jul 30.

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

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Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Llobregat, Spain.
Cell Culture Platform and Division of Neurosciences.
Division of Neurosciences, Instituto Biodonostia, San Sebastián, Spain Department of Neurology, Hospital Universitario Donostia, San Sebastián, Spain CIBERNED, Centro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas, Instituto Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain and Department of Neurosciences, University of the Basque Country UPV-EHU, San Sebastián, Spain.
Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain


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.

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