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Autoimmune Mechanisms in the Gut are Silent Drivers of Parkinsons's Disease

New findings in mice suggest autoimmune mechanisms that originate in the gut are silent drivers of Parkinson’s disease

Parkinson’s disease is caused by the progressive loss of dopaminergic neurons and recent studies have widened the immune system and the gut microbiota‘s contribution to the disease.

A new study in mice, led by researchers from the Université de Montréal and McGill University in Canada, shows the involvement of intestinal infections as a trigger in Parkinson’s disease through autoimmune mechanisms.

Previous in vitro and in vivo data showed that mutations in the genes PINK1 and PRKN are involved in the autophagy of damaged mitochondria (commonly referred to as mitophagy) and also play an active role in repressing mitochondrial antigen presentation. These findings suggest that autoimmune mechanisms could likely be involved in Parkinson’s disease.

However, the fact that contradictory findings have also been observed in mice led Matheoud and colleagues to explore other triggers.

In the current study, the infection of mice that did not express PINK1 and/or PRKN with the Gram-negative bacterium Citrobacter rodentium triggered mitochondrial antigen presentation in the periphery. Furthermore, the intestinal infection led to cytotoxic CD8+ T cells being established, which targeted dopaminergic neurons in the brain, whereas non-dopaminergic neurons were not affected.

The induction of microbial antigen presentation was also found after infecting mouse macrophage-like cell lines with Gram-negative bacteria (even when heat-killed) but not with Gram-positive bacteria, whereas it was abolished in the presence of Parkin (encoded by PRKN).

Furthermore, infected mice also showed a more than 40% drop in the number of dopaminergic axons in the striatum, along with motor impairment—both classic Parkinson’s disease-like markers—which was reversed after treatment with L-DOPA.

On the whole, these preliminary findings in mice show that PINK1 kinase genes are major repressors of adaptive immune responses and their absence may contribute to the development of Parkinson’s disease under a stressor, such as an intestinal infection.

The contribution of autoimmune mechanisms to Parkinson’s disease opens up new avenues for developing preventive therapeutic approaches. Other origins of Parkinson’s disease involving the gut-brain axis are also currently the subject of active research.

Reference:

Matheoud D, Cannon T, Voisin A, et al. Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1-/- miceNature. 2019. doi: 10.1038/s41586-019-1405-y.

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