Gut infection in PINK1-knockout mice

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Diana Matheoud, Michel Desjardins, Heidi McBride, Louis-Eric Trudeau, Samantha Gruenheid and colleagues, Université de Montréal (CRCHUM), the Montreal Neurological Institute and McGill University; funded by the Canadian Institutes of Health Research, Brain Canada, the Krembil Foundation and the Michael J. Fox Foundation (per a press-release summary).

What happened

PINK1 gene mutations cause early-onset Parkinson's (landmark 15). The same group had found that PINK1 and parkin normally suppress mitochondrial antigen presentation, where immune cells display mitochondrial fragments (landmark 126).

Here, Pink1 knockout mice were given an intestinal infection with the Gram-negative bacterium Citrobacter rodentium (named in Nature's News & Views; the abstract says only Gram-negative bacteria). In these mice the abstract reports that:

• mitochondrial antigen presentation was engaged;
• cytotoxic (cell-killing) CD8+ T cells specific to mitochondrial proteins appeared in the body and the brain;
• there was a sharp drop in the density of dopamine-axon endings in the striatum;
• the mice showed motor impairment that levodopa reversed.

The authors say PINK1 acts as a brake on the immune system and propose intestinal infection as a trigger of Parkinson's.

Why it moved us toward a cure

It joined three branches in one model: inherited mitochondrial genes, immunity and the gut. If genes plus infection can start disease, it suggests immune-modulating or infection-preventing steps for gene carriers. This is a mouse model that does not prove the same occurs in people.

Outcome

Open. It has not been tested in people. The abstract reports loss of dopamine nerve endings (axonal varicosities) in the striatum, not loss of nigral neurons. A Nature News & Views commentary noted that the motor deficits and loss of dopamine release sites had reversed one year after infection without treatment, and that non-motor symptoms were not examined. The infection-plus-gene idea remains a hypothesis. I found no correction or retraction.

Sources

• Matheoud et al., Nature 2019;571:565–569, DOI 10.1038/s41586-019-1405-y, PMID 31316206 (abstract via Europe PMC)
• Nature News & Views on Matheoud et al., 2019, DOI 10.1038/d41586-019-02094-6
• Neuroscience News summary (institutions, funders)
• Not yet verified: mouse numbers and ages; whether the findings were replicated; Alzforum coverage.