Study Uncovers Molecular Mechanism of Protein Linked to Early-onset Parkinson’s
These results suggest that the protein may be implicated in the development of Parkinson’s, specifically the brain inflammation and loss of neurons associated with the disease. This discovery may support the development of treatments that slow Parkinson’s progression by helping rescue neurons that would otherwise die.
The study, “Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy” was published in the EMBO Journal.
Lack of the PRKN gene, which codes for the Parkin protein, or mutations that result in faulty Parkin protein are known drivers of early-onset Parkinson’s disease. Understanding how this protein influences cell survival can provide insight on how it works and why its deficiency promotes neurodegenerative conditions such as Parkinson’s.
Now, a team led by researchers at the Walter and Eliza Hall Institute of Medical Research and the University of Melbourne, Australia, investigated the cell-protective role of Parkin and conducted experiments in different cell types grown in the laboratory, engineered to express a normal and functional Parkin protein or mutant versions associated with Parkinson’s disease.
The results showed that Parkin was able to block cell death by inhibiting a protein called BAK.
BAK and a related protein, called BAX, are activated in response to cellular damage, setting up a programmed cellular death cascade referred to as apoptosis.
An important part of this process is the dismantling of mitochondria, structures that supply energy to cells. Damage to mitochondria may itself trigger apoptosis and inflammation, warning neighboring cells of a potential danger.
In these conditions, Parkin tags BAK with a small protein called ubiquitin that signals cells to limit BAK’s activity. Ubiquitin is part of a “quality control” system by which cells dispose of damaged, misshapen, or excess proteins.
By suppressing BAK, Parkin halts cell death and promotes clearance of damaged mitochondria, limiting their potential for inducing inflammation.
“Parkin ‘buys time’ for the cell, allowing the cell’s innate repair mechanisms to respond to the damage,” Grant Dewson, Ph.D., associate professor at the Walter and Eliza Hall Institute and senior author of the study, said in a press release.
“In a healthy brain, Parkin helps keep cells alive, and decreases the risk of harmful inflammation by repairing damage to mitochondria,” said study author Jonathan Bernardini.
The data showed that without Parkin or with faulty variants of it, BAK is not tagged and excessive cell death can occur. This may contribute to nerve cell loss typical of Parkinson’s disease, researchers said.
“Drugs that can stifle BAK, mimicking the effect of Parkin, may have the potential to reduce harmful cell death in the brain,” Dewson said.
These insights expanded on the knowledge of how neuron death and brain inflammation may occur in Parkinson’s disease. This might help foster new therapies to slow the progression of the disease.