Studies by researchers at Montreal University have found that a mild gut infection can result in motor symptoms and brain pathology resembling Parkinson’s disease (PD) in mice that carry a gene mutation known to be associated with the disorder in humans. The studies suggest that in animals lacking the PINK1 gene, a gut infection causes overstimulation of the immune system, which triggers an autoimmune reaction that kills dopaminergic neurons in the brain. The results add further weight to accumulating evidence implicating the gut-brain axis in PD.
“Although further research is needed to understand fully the mechanism, relevance, and implications of these findings for human disease, our data provide evidence that an autoimmune response engaged in the absence of PINK1 during intestinal infection participates in the etiology of Parkinson’s disease,” the authors concluded in their published paper in Nature, which is titled, “Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1-/- mice”.
Parkinson’s disease is a neurodegenerative disorder associated with progressively worsening motor symptoms and the loss of dopaminergic neurons in the substantia nigra compacta region of the brain. “Most of the current models of PD are based on the belief that neurons die due to toxic elements accumulating inside them,” said research co-lead Louis-Eric Trudeau, PhD, a Université de Montréal neuroscientist. “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 exact mechanisms that trigger loss of dopaminergic neurons in PD are also unclear, but mitochondrial dysfunction and inflammation are thought to have key roles, suggested Trudeau and co-researchers Michel Desjardins, PhD, and Heidi McBride, PhD, at the Montreal Neurological Institute, and Samantha Gruenheid, PhD, at McGill University.
In humans, about 10% of PD cases are due to mutations in the genes for PINK1 kinase, and Parkin, but Pink1-/- and Prkn-/- mice that lack these genes generally stay healthy and don’t develop the motor symptoms characteristic of the human disease. “Thus, factors other than the loss of function of these proteins are likely to be required to trigger Parkinson’s disease pathophysiology,” the authors continued.
Their studies have now shown that setting up a mild bacterial gut infection in Pink1-/- mice triggers autoimmune mechanisms that lead to the production of cytotoxic, mitochondria-specific CD8+ T cells that can spread to the brain. Such autoreactive cytotoxic T lymphocytes were also able to attack healthy neurons in culture dishes. “We observed mitochondria-specific CD8+ T cells within the brain of infected Pink1-/- mice and demonstrated their capacity to kill dopaminergic neurons in vitro,” the team noted.
Within four months of gastrointestinal infection, the Pink1-/- mice developed the type of motor dysfunction that is typical in PD patients and in a rat model of PD, and they also demonstrated loss of dopaminergic neurons in the brain. Interestingly, motor symptoms in these Pink1-/- mice could be reversed temporarily by treatment with L-DOPA, a drug that is used to treat PD in humans.
It is generally assumed that motor dysfunction in PD patients start only after there has been considerable loss of dopaminergic neurons, but the Montreal University team’s results also indicated that the terminals of dopaminergic neurons are affected well before the nerve cells are killed, “providing a window of opportunity for therapeutic intervention.”
The results support the idea that PINK1 is a repressor of the immune system, the researchers concluded. “The discovery that intestinal infection transforms asymptomatic Pink1-/- mice into a fully penetrant model, presenting with acute motor symptoms that are reversed after treatment with L-DOPA, adds to the growing body of evidence that implicates the gut–brain axis in Parkinson’s disease … This also provides a model to characterize the onset of Parkinson’s disease and develop therapeutic approaches.”