Parkinson’s disease related proteins PINK1 and Parkin are major regulators of the immune system

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder linked to the loss of dopaminergic neurons (DN) in the substantia nigra. Although the mechanisms triggering the loss of DN are unclear, mitochondrial dysfunction and inflammation are viewed as playing a key role. PINK1 and Parkin are major regulators of mitophagy and failure in this pathway in DNs is hypothesized to enhanced oxidative stress and cause cell death. However, we showed that PINK1 and Parkin play also a role in adaptive immunity by repressing mitochondrial antigen presentation (MitAP) (Matheoud et al., Cell 2016), suggesting that autoimmune mechanisms participate in the aetiology of PD. Here, following on the finding that LPS triggers MitAP in vitro and in vivo, we present evidence that intestinal infection with Gram - bacteria in Pink1 KO mice increases the release of pro-inflammatory cytokines, activates MitAP and induces autoimmune mechanisms eliciting the activation of cytotoxic mitochondria-specific CD8+ T cells. Remarkably, infection in these mice also leads to the emergence of severe motor impairment, reversed by L-DOPA treatment, accompanied by a sharp decrease in the density of dopaminergic axonal varicosities in the striatum. These data support the role of PINK1 as a modulator of the immune system and provide a new pathophysiological model where intestinal infection acts as a triggering event in PD, highlighting the relevance of the gut-brain axis in the disease.

Reduced penetrance of Parkinson’s disease models

“…Interestingly, the G2019S LRRK2 mutation is abundantly present in both sporadic and familial forms of PD [ 54 ]; however, it has a surprisingly low penetrance [ 53 ], further supporting the existence of a second hit model for PD that involves inflammation. Interestingly, other genes involved in PD, including PINK1 and Parkin, function in immunity [ 55 ], further supporting the important role of inflammation in PD.…”