TY  - JOUR
AU  - Funk, Natalja
AU  - Munz, Marita
AU  - Ott, Thomas
AU  - Brockmann, Kathrin
AU  - Wenninger-Weinzierl, Andrea
AU  - Kühn, Ralf
AU  - Vogt-Weisenhorn, Daniela
AU  - Giesert, Florian
AU  - Wurst, Wolfgang
AU  - Gasser, Thomas
AU  - Biskup, Saskia
TI  - The Parkinson's disease-linked Leucine-rich repeat kinase 2 (LRRK2) is required for insulin-stimulated translocation of GLUT4.
JO  - Scientific reports
VL  - 9
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DZNE-2020-06888
SP  - 4515
PY  - 2019
AB  - 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.
KW  - Animals
KW  - Cell Survival: drug effects
KW  - Fibroblast Growth Factors: pharmacology
KW  - Fibroblasts: cytology
KW  - Fibroblasts: metabolism
KW  - Glucose Transporter Type 4: metabolism
KW  - Humans
KW  - Insulin: pharmacology
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
KW  - Mice
KW  - Neuronal Outgrowth: drug effects
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: pathology
KW  - Phosphorylation
KW  - Polymorphism, Single Nucleotide
KW  - Proto-Oncogene Proteins c-akt: metabolism
KW  - Rats
KW  - Signal Transduction: drug effects
KW  - rab GTP-Binding Proteins: metabolism
LB  - PUB:(DE-HGF)16
C6  - pmid:30872638
C2  - pmc:PMC6418296
DO  - DOI:10.1038/s41598-019-40808-y
UR  - https://pub.dzne.de/record/140566
ER  -