Researchers have identified an interactive triangle of proteins whose activity may be regulated to prevent loss of the brain’s dopaminergic neurons, whose diminishment leads to Parkinson’s disease.
One of these proteins, called PARIS, contributes to the death of the neurons. Targeting it could lead to therapies for Parkinson’s, the researchers said.
Their study, “PINK1 Primes Parkin-Mediated Ubiquitination Of PARIS In Dopaminergic Neuronal Survival” was published in the journal Cell Reports,
The death of dopaminergic neurons causes symptoms of Parkinson’s, including tremors and impaired movement. Mutations in two proteins called Parkin and PINK1 contribute to this effect. Dopaminergic neurons are the main source of dopamine, a chemical that sends signals to the nerves.
Ted Dawson and his research colleagues at Johns Hopkins University had already discovered that Parkin signaled other proteins to eliminate PARIS. That stopped the toxic accumulation of PARIS in dopaminergic neurons, preventing their loss.
The team’s latest finding is that PINK1 also interacts with PARIS to regulate PARIS’s levels.
Using a series of laboratory experiments, the researchers observed that PINK1 works by tagging PARIS with a phosphate group. The tagging allows Parkin to target PARIS.
Mutant forms of PINK1 do not work properly, however, leading to an accumulation of PARIS and an increase in dopaminergic neuron death.
Researchers now realize that PARIS is at the center of both Parkin and PINK1’s protective activity in the brain. A key implication is that faulty versions of the two proteins can be remedied by treatments targeting PARIS.
“Mutations in the genes for both Parkin and PINK1 have now been linked to Parkinson’s disease,” Dawson said in a news release. “Parkin is a particularly big player that seems to be at fault in many inherited cases; it’s also inactivated in sporadic cases of the disease. So a drug targeting PARIS could potentially help many patients.”
Although pre-treatment and therapy-design studies are necessary to validate the results, Dawson believes the team’s research not only provides valuable insight into the molecular mechanisms behind Parkinson’s but also could lead to targeted treatments for the disease.