TY  - JOUR
AU  - Kuß, Martin
AU  - Adamopoulou, Eleni
AU  - Kahle, Philipp J
TI  - Interferon-γ induces leucine-rich repeat kinase LRRK2 via extracellular signal-regulated kinase ERK5 in macrophages.
JO  - Journal of neurochemistry
VL  - 129
IS  - 6
SN  - 0022-3042
CY  - Oxford
PB  - Wiley-Blackwell
M1  - DZNE-2020-03756
SP  - 980-987
PY  - 2014
AB  - The gene encoding leucine-rich repeat kinase 2 (LRRK2) comprises a major risk factor for Parkinson's disease. Recently, it has emerged that LRRK2 plays important roles in the immune system. LRRK2 is induced by interferon-γ (IFN-γ) in monocytes, but the signaling pathway is not known. Here, we show that IFN-γ-mediated induction of LRRK2 was suppressed by pharmacological inhibition and RNA interference of the extracellular signal-regulated kinase 5 (ERK5). This was confirmed by LRRK2 immunostaining, which also revealed that the morphological responses to IFN-γ were suppressed by ERK5 inhibitor treatment. Both human acute monocytic leukemia THP-1 cells and human peripheral blood monocytes stimulated the ERK5-LRRK2 pathway after differentiation into macrophages. Thus, LRRK2 is induced via a novel, ERK5-dependent IFN-γ signal transduction pathway, pointing to new functions of ERK5 and LRRK2 in human macrophages. Leucine-rich repeat kinase 2 (LRRK2) is a major risk factor for the development of Parkinson's disease (PD). However, the role of LRRK2 in the affected neurons remains enigmatic. Recently, LRRK2 has been reported to be strongly expressed in the immune system. Here, we demonstrate that LRRK2 is induced by Interferon gamma via extracellular signal-regulated kinase 5 (ERK5) in macrophages, thus providing new insights in LRRK2 and ERK5 biology.
KW  - Protein Serine-Threonine Kinases: biosynthesis
KW  - Blotting, Western
KW  - Cells, Cultured
KW  - Cytokines: metabolism
KW  - Enzyme Induction: drug effects
KW  - Enzyme Inhibitors: pharmacology
KW  - Humans
KW  - Immunohistochemistry
KW  - Interferon-gamma: antagonists & inhibitors
KW  - Interferon-gamma: pharmacology
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
KW  - Macrophages: drug effects
KW  - Macrophages: enzymology
KW  - Mitogen-Activated Protein Kinase 7: antagonists & inhibitors
KW  - Mitogen-Activated Protein Kinase 7: physiology
KW  - Protein-Serine-Threonine Kinases: biosynthesis
KW  - Real-Time Polymerase Chain Reaction
KW  - Signal Transduction: drug effects
KW  - Cytokines (NLM Chemicals)
KW  - Enzyme Inhibitors (NLM Chemicals)
KW  - Interferon-gamma (NLM Chemicals)
KW  - LRRK2 protein, human (NLM Chemicals)
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
KW  - Protein-Serine-Threonine Kinases (NLM Chemicals)
KW  - Mitogen-Activated Protein Kinase 7 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24479685
DO  - DOI:10.1111/jnc.12668
UR  - https://pub.dzne.de/record/137434
ER  -