In 1984, the great Muhammed Ali had to retire from his legendary boxing career. Later, in the early 2000s, Michael J. Fox was forced to retire from acting for the same reason: Parkinson’s Disease. It is a neurodegenerative disease that afflicts about one million people in the United States alone with worldwide estimates ranging from four to six million patients.
As the second most common neurodegenerative condition behind Alzheimer’s, scientists have been striving to find a cure for decades. Here at Hopkins, the Leonard and Madlyn Abramson Professor of Neurodegenerative Diseases, Ted Dawson, has further elucidated the molecular mechanisms that underlie Parkinson’s Disease.
10 years ago, a Japanese lab published a groundbreaking paper that explained how parkin, an E3 ubiquitin ligase, was involved in Parkinson’s disease. “The cells are little machines, and parts need to be repaired, damaged parts need to be removed, and new ones need to be replaced so parkin normally works in the maintenance and removal of the damaged proteins,” said Dawson.
Normally, parkin would direct ubiquitin to various proteins that have built up around neurons. Ubiquitin then targets the proteins for degradation. Mutant parkin, however, has lost this function and so the proteins are allowed to accumulate around the neurons, eventually leading to toxicity.
Dawson and his team showed that parkin regulates PARIS, a repressor of PGC-1 alpha, which is essential for the biogenesis of mitochondria. Mutated parkin then allows PARIS to accumulate, increasing the inhibition of PGC-1 alpha.
“PGC-1 alpha is a very important regulator of mitochondrial function, so cells aren’t able to make new mitochondria,” explained Dawson. “The cell isn’t able to respond to stress, to the normal process of regulating cell turnover.” Consequently, the neurons begin to degrade, leading to the symptoms indicative of Parkinson’s disease.
Dawson has been interested in Parkinson’s Disease since his years as a student in the MD/Ph.D program at the University of Utah School of Medicine. During his current experiments, he read a Nature paper that discussed how genes could be knocked out in adulthood rather than during embryonic development to achieve neurodegeneration.
His lab incorporated this news into their study to see how important a role PARIS played in Parkinson’s. They had mice that were knocked out for the parkin gene. Dawson’s lab went further and knocked out PARIS, creating double-knockouts. “We used what’s called shRNA, a method which prevents the transcription of the gene for PARIS, so it lowers the levels of the mRNA for PARIS, which is translated into lowering the protein levels,” said Dawson of their methods. “We had to use something faster — we’d still be doing the experiment if we knocked it out otherwise,” he said.
They found that PGC-1 alpha levels rose and neurodegeneration halted, indicating that PARIS is a key aspect of Parkinson’s. Particularly exciting about this research is the hope for treatment options. “One could envision and develop inhibitors of PARIS, so we have a big focus right now on trying to come up with inhibitors that will inhibit PARIS and then enhance PGC-1 alpha function,” said Dawson.
“This would be a major new therapeutic class for Parkinson’s disease neuroprotection.” Gene therapies may be promising, considering that Dawson and his team know that at least in the mouse they can knock down PARIS. “I would say it should work so that would be in the short term, but in the long term, we hope to find a drug you can take.”
There are two established classifications of Parkinson’s Disease: autosomal recessive and late-onset sporadic, which is the far more common form that begins to show symptoms in the elderly. Dawson believes that both types should respond well to the same treatments. However, end-stage Parkinson’s patients may not be so fortunate. “Once all of the neurons are dead, then treatment would have to be with cell replacement,” explained Dawson. “But I would say that treatment for pre-symptomatic and mid-stage Parkinson’s should be very beneficial.” Dawson emphasized that the future of Parkinson’s disease therapy is really exciting and that he and his team are very encouraged with their progress so far. “We’re just hoping that this will lead to new and important treatments for Parkinson’s.”
