Abstract
Neuroinflammation is involved in the pathogenesis of Parkinson’s disease (PD) and other neurodegenerative disorders. We show that lack of PINK1- a mitochondrial kinase linked to recessive familial PD – leads to glia type-specific abnormalities of innate immunity. PINK1 loss enhances LPS/IFN-γ stimulated pro-inflammatory phenotypes of mixed astrocytes/microglia (increased iNOS, nitric oxide and COX-2, reduced IL-10) and pure astrocytes (increased iNOS, nitric oxide, TNF-α and IL-1β), while attenuating expression of both pro-inflammatory (TNF-α, IL-1β) and anti-inflammatory (IL-10) cytokines in microglia. These abnormalities are associated with increased inflammation-induced NF-κB signaling in astrocytes, and cause enhanced death of neurons co-cultured with inflamed PINK1−/− mixed glia and neuroblastoma cells exposed to conditioned medium from LPS/IFN-γ treated PINK1−/− mixed glia. Neuroblastoma cell death is prevented with an iNOS inhibitor, implicating increased nitric oxide production as the cause for enhanced death. Finally, we show for the first time that lack of a recessive PD gene (PINK1) increases α-Synuclein-induced nitric oxide production in all glia types (mixed glia, astrocytes and microglia). Our results describe a novel pathogenic mechanism in recessive PD, where PINK1 deficiency may increase neuron death via exacerbation of inflammatory stimuli-induced nitric oxide production and abnormal innate immune responses in glia cells.
Highlights
Neuroinflammation plays an important role in the pathogenesis of PD1,2
We show that loss of PINK1 alters LPS/IFN-γ induced neuroinflammation in a glia type-specific manner, increasing pro-inflammatory mediators in astrocytes (TNF-α, IL-1β and nitric oxide (NO)) and in mixed glia (NO), while attenuating both pro-inflammatory (TNF-α, IL-1β) and anti-inflammatory (IL-10) mechanisms in microglia
The finding that IL-10 expression is lower in PINK1−/− microglia provides a mechanistic explanation for the cytokine profile and NO production observed in PINK1−/− astrocytes and mixed glia
Summary
Neuroinflammation plays an important role in the pathogenesis of PD1,2. Brain inflammation contributes to the neuropathology in toxin-induced models of PD2. Relatively few studies have addressed the importance of recessive PD genes in neuroinflammation, expression of PINK1, Parkin and DJ-1 is increased in reactive astrocytes in the diseased human brain[17,18,19], suggesting that these proteins affect or regulate glia-dependent immune responses. We show that lack of PINK1 differentially affects inflammation-induced gene expression and NO production in astrocytes, microglia and mixed astrocytes/microglia. These changes are associated with increased apoptosis of normal primary WT neurons co-cultured with PINK1-deficient mixed glia. Our results suggest that PINK1 deficiency in recessive familial Parkinsonism may increase neuron death via exacerbation of inflammatory stimuli-induced NO production and abnormal innate immune responses in glia cells
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