Funk N1, Munz M2, Ott T3, Brockmann K2, Wenninger-Weinzierl A2, Kühn R4,5, Vogt-Weisenhorn D5, Giesert F5, Wurst W5,6, Gasser T2, Biskup S7.
Abstract
Mutations within Leucine-rich repeat kinase 2 (LRRK2) are associated with late-onset Parkinson’s disease. The physiological function of LRRK2 and molecular mechanism underlying the pathogenic role of LRRK2 mutations remain uncertain. Here, we investigated the role of LRRK2 in intracellular signal transduction. We find that deficiency of Lrrk2 in rodents affects insulin-dependent translocation of glucose transporter type 4 (GLUT4). This deficit is restored during aging by prolonged insulin-dependent activation of protein kinase B (PKB, Akt) and Akt substrate of 160 kDa (AS160), and is compensated by elevated basal expression of GLUT4 on the cell surface. Furthermore, we find a crucial role of Rab10 phosphorylation by LRRK2 for efficient insulin signal transduction. Translating our findings into human cell lines, we find comparable molecular alterations in fibroblasts from Parkinson’s patients with the known pathogenic G2019S LRRK2 mutation. Our results highlight the role of LRRK2 in insulin-dependent signalling with potential therapeutic implications.
- Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University Clinic Tuebingen, Tuebingen, Germany. natalja.funk@medizin.uni-tuebingen.de.
- Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University Clinic Tuebingen, Tuebingen, Germany.
- IZKF Facility for Transgenic Animals, Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
- Max-Delbrueck-Center for Moleculare Medizin and Berlin Institute of Health, Berlin, Germany.
- Helmholtz Zentrum Muenchen, Technical University Muenchen-Weihenstephan, Institute of Developmental Genetics, Neuherberg, Germany.
- German Center for Neurodegenerative Diseases, Munich, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
- Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University Clinic Tuebingen, Tuebingen, Germany. saskia.biskup@medizin.uni-tuebingen.de.