Abstract
BackgroundOver-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.MethodsHere, 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.ResultsInhibition 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.ConclusionsTaken 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.
Highlights
Over-activated microglia and chronic neuroinflammation contribute to dopaminergic neuron degeneration and progression of Parkinson’s disease (PD)
We showed that Leucine-rich repeat kinase 2 (LRRK2) takes part of the signaling trigged by α-synuclein (α-syn) fibrils, which culminates in microglia activation and induction of inflammatory IL-1β cytokine
These results indicate that LRRK2 kinase activity modulates the inflammatory response in microglia cells
Summary
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. In cultured microglia cells, the kinase was suggested to regulate the activity of the transcription factor nuclear factor kappa-B (NF-κB) through a yet unknown mechanism [24]. NF-κB p65 bound to IκBs inhibitory proteins is phosphorylated at S536 by the IKK complex upon an inflammatory stimulus This results in IκBs proteasomal degradation and release of NF-κB p65:p50 dimers that enter the nucleus and activate transcription of target genes [30]. The activated p65:p50 heterodimers are able to bind DNA and induce gene expression by displacing the p50:p50 homodimers [27]
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