Intestinal infection triggers Parkinson's like symptoms

Intestinal infection triggers Parkinson's like symptoms


A new study by  scientists published in Nature demonstrates that a gut infection can lead to a pathology resembling Parkinson's disease (PD) in a mouse model lacking a gene linked to the human disease.

This discovery extends recent work by the same group suggesting that PD has a major immune component, providing new avenues for therapeutic strategies.

About 10 per cent of cases of PD are due to mutations in genes coding for proteins such as PINK1 and Parkin, which have been linked to mitochondria (the organelle in cells that produces energy). Patients with these mutations develop PD at a much earlier age. However, in mouse models, the same mutations do not generate disease symptoms, leading many researchers to conclude that mice may not be suitable for the study of PD.

The findings in this new study may explain this disparity: these animals are normally kept in germ-free facilities, conditions not representative of those encountered by human beings who are constantly exposed to infectious microorganisms.

PD is caused by the progressive death of a subset of neurons in the brain, called dopaminergic neurons. This loss of neurons is responsible for the typical motor symptoms observed in PD patients, including tremors and rigidity. What causes the death of the dopaminergic neurons is still unknown.

"Most of the current models of PD are based on the belief that neurons die due to toxic elements accumulating inside them," said the author. "This does not explain, however, the fact that PD pathology is initiated in patients several years before the emergence of the motor impairment and any noticeable loss of neurons."

The reason for this is believed to be explained by the results of the present study. The team has shown that in mice lacking a gene linked to PD, infection with bacteria that cause mild intestinal symptoms in young mice was sufficient to trigger PD-like symptoms in these animals later in life.

The infection with Gram-negative bacteria in Pink1−/− mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. 

 The authors point out that in normal mice, the immune system responded properly to the gut infection; however, in mice lacking the gene PINK1 related to Parkinson's, the immune system overreacted and triggered "auto-immunity", a process that leads the immune system to attack healthy cells in the organism. The results published suggest that rather than dying from toxin accumulation, the killing of dopaminergic neurons involves immune cells.

In the infected mutant mice, autoreactive toxic T lymphocytes were shown to be present in the brain and able to attack healthy neurons in culture dishes. The co-first authors of the published article, emphasize the fact that these results strongly suggest that some forms of PD are an autoimmune disease likely to start in the gut several years before patients notice any motor symptoms, highlighting the fact that a window of time exists for preventive treatment.

https://nouvelles.umontreal.ca/article/2019/07/17/la-maladie-de-parkinson-pourrait-elle-etre-declenchee-par-une-infection-intestinale/

https://www.nature.com/articles/s41586-019-1405-y

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