Title |
Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-κB p50 signaling in cultured microglia cells
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Published in |
Journal of Neuroinflammation, December 2015
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DOI | 10.1186/s12974-015-0449-7 |
Pubmed ID | |
Authors |
Isabella Russo, Giulia Berti, Nicoletta Plotegher, Greta Bernardo, Roberta Filograna, Luigi Bubacco, Elisa Greggio |
Abstract |
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. 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. 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. 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. |
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Unknown | 99 | 98% |
Demographic breakdown
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Student > Master | 15 | 15% |
Researcher | 13 | 13% |
Student > Bachelor | 8 | 8% |
Student > Doctoral Student | 7 | 7% |
Other | 12 | 12% |
Unknown | 22 | 22% |
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Medicine and Dentistry | 12 | 12% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 6% |
Other | 3 | 3% |
Unknown | 26 | 26% |