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@ARTICLE{Funk:140566,
author = {Funk, Natalja and Munz, Marita and Ott, Thomas and
Brockmann, Kathrin and Wenninger-Weinzierl, Andrea and
Kühn, Ralf and Vogt-Weisenhorn, Daniela and Giesert,
Florian and Wurst, Wolfgang and Gasser, Thomas and Biskup,
Saskia},
title = {{T}he {P}arkinson's disease-linked {L}eucine-rich repeat
kinase 2 ({LRRK}2) is required for insulin-stimulated
translocation of {GLUT}4.},
journal = {Scientific reports},
volume = {9},
number = {1},
issn = {2045-2322},
address = {[London]},
publisher = {Macmillan Publishers Limited, part of Springer Nature},
reportid = {DZNE-2020-06888},
pages = {4515},
year = {2019},
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.},
keywords = {Animals / Cell Survival: drug effects / Fibroblast Growth
Factors: pharmacology / Fibroblasts: cytology / Fibroblasts:
metabolism / Glucose Transporter Type 4: metabolism / Humans
/ Insulin: pharmacology / Leucine-Rich Repeat
Serine-Threonine Protein Kinase-2: genetics / Leucine-Rich
Repeat Serine-Threonine Protein Kinase-2: metabolism / Mice
/ Neuronal Outgrowth: drug effects / Parkinson Disease:
metabolism / Parkinson Disease: pathology / Phosphorylation
/ Polymorphism, Single Nucleotide / Proto-Oncogene Proteins
c-akt: metabolism / Rats / Signal Transduction: drug effects
/ rab GTP-Binding Proteins: metabolism},
cin = {Tübingen Pre 2020 / Ext UKT / AG Gasser 1 / AG Haass old /
AG Wurst},
ddc = {600},
cid = {I:(DE-2719)6000018 / I:(DE-2719)5000058 /
I:(DE-2719)1210000 / I:(DE-2719)1110007 /
I:(DE-2719)1140001},
pnm = {345 - Population Studies and Genetics (POF3-345) / 342 -
Disease Mechanisms and Model Systems (POF3-342)},
pid = {G:(DE-HGF)POF3-345 / G:(DE-HGF)POF3-342},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30872638},
pmc = {pmc:PMC6418296},
doi = {10.1038/s41598-019-40808-y},
url = {https://pub.dzne.de/record/140566},
}