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J Neuroinflammation. 2015 Dec 9;12:230. doi: 10.1186/s12974-015-0449-7.

Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-κB p50 signaling in cultured microglia cells.

Author information

1
Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy.
2
Current address: Department of Cell and Developmental Biology, University College London, London, UK.
3
Current address: Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
4
Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy. elisa.greggio@unipd.it.

Abstract

BACKGROUND:

Over-activated microglia and chronic neuroinflammation contribute to dopaminergic neuron degeneration and progression of Parkinson's disease (PD). Leucine-rich repeat kinase 2 (LRRK2), a kinase mutated in autosomal dominantly inherited and sporadic PD cases, is highly expressed in immune cells, in which it regulates inflammation through a yet unclear mechanism.

METHODS:

Here, using pharmacological inhibition and cultured Lrrk2 (-/-) primary microglia cells, we validated LRRK2 as a positive modulator of inflammation and we investigated its specific function in microglia cells.

RESULTS:

Inhibition or genetic deletion of LRRK2 causes reduction of interleukin-1β and cyclooxygenase-2 expression upon lipopolysaccharide-mediated inflammation. LRRK2 also takes part of the signaling trigged by α-synuclein fibrils, which culminates in induction of inflammatory mediators. At the molecular level, loss of LRRK2 or inhibition of its kinase activity results in increased phosphorylation of nuclear factor kappa-B (NF-κB) inhibitory subunit p50 at S337, a protein kinase A (PKA)-specific phosphorylation site, with consequent accumulation of p50 in the nucleus.

CONCLUSIONS:

Taken together, these findings point to a role of LRRK2 in microglia activation and sustainment of neuroinflammation and in controlling of NF-κB p50 inhibitory signaling. Understanding the molecular pathways coordinated by LRRK2 in activated microglia cells after pathological stimuli such us fibrillar α-synuclein holds the potential to provide novel targets for PD therapeutics.

PMID:
26646749
PMCID:
PMC4673731
DOI:
10.1186/s12974-015-0449-7
[Indexed for MEDLINE]
Free PMC Article

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