title: LRRK2 delays degradative receptor trafficking by impeding late endosomal budding through decreasing Rab7 activity.
abstract: 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.
authors: Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors: Patricia
authors: P
authors: Gómez-Suaga
authors: Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors: Pilar
authors: P
authors: Rivero-Ríos
authors: Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors: Elena
authors: E
authors: Fdez
authors: Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain.
authors: Marian
authors: M
authors: Blanca Ramírez
authors: Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Llobregat, Spain.
authors: Isidro
authors: I
authors: Ferrer
authors: Cell Culture Platform and Division of Neurosciences.
authors: Ana
authors: A
authors: Aiastui
authors: 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.
authors: Adolfo
authors: A
authors: López De Munain
authors: Institute of Parasitology and Biomedicine 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Avda del Conocimiento s/n, 18016 Granada, Spain sabine.hilfiker@ipb.csic.es.
authors: Sabine
authors: S
authors: Hilfiker
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010957:Plasmids; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D059748:Proteolysis; D015398:Signal Transduction; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins