Like all living things, cellular structures break down over time and must be recycled. In cells, this process is called autophagy. Most neurodegenerative diseases are related to the improper accumulation of cellular waste by-products. Now, for the first time, researchers at the Hospital for Sick Children (SickKids) have revealed a way to potentially reduce the amount of toxic cellular waste accumulating in patients with Zellweger Spectrum Disorder (ZSD). The researchers discovered that by genetically and pharmaceutically increasing a cell’s ability to recycle its own components it is possible to clear damaged cellular material, providing a new therapeutic target for treating ZSD. The new findings may also inform research in other neurodegenerative conditions such as Huntington’s disease and Parkinson’s disease.
The findings are published in Nature Communications in an article titled, “Upregulated pexophagy limits the capacity of selective autophagy,” and led by Peter Kim, PhD, a senior scientist in the cell biology program at SickKids, and Robert Bandsma, PhD, a scientist in the translational medicine program.
“Selective autophagy is an essential process to maintain cellular homeostasis through the constant recycling of damaged or superfluous components,” the researchers wrote. “Over a dozen selective autophagy pathways mediate the degradation of diverse cellular substrates, but whether these pathways can influence one another remains unknown. We address this question using pexophagy, the autophagic degradation of peroxisomes, as a model.”
ZSD is a group of rare, neurodegenerative genetic conditions caused by genetic variations that reduce the number of peroxisomes, which are the parts of cells that are responsible for, among other tasks, breaking down fats. ZSD varies in severity and is characterized by progressive neurodegeneration as well as symptoms that range from visual impairments, such as cataracts, to liver and kidney dysfunction.
Previous research from the Kim-Bandsma team found that the most common genetic variation that causes ZSD significantly increases pexophagy, causing healthy peroxisomes to get recycled alongside unhealthy ones. In the new study, Kyla Germain, PhD, a former graduate student in Kim’s and Bandsma’s labs, found that this increase in pexophagy can also prevent cells from degrading other cellular waste.
“Our work demonstrates for the first time that different cellular recycling pathways can influence one another,” Germain explained. “A cell’s recycling system has a maximum load capacity—an autophagic limit. When this limit is exceeded, toxic cellular waste will accumulate.”
After identifying this connection between different recycling pathways, researchers found they could improve the overall recycling process by increasing the autophagic limit. In doing so, they observed improved clearance of cellular waste, which opens new pathways to treat ZSD.
“These results are exciting as they show that through understanding a fundamental process that takes place in all our cells, we can potentially develop new and better treatments for a very serious condition,” said Bandsma, who is also a staff physician in the division of gastroenterology, hepatology, and nutrition at SickKids.
“We identified that protein aggregates involved in Huntington’s disease and Parkinson’s disease can also prevent the turnover of damaged peroxisomes, which means scientists may be able to target these components in patients outside the field of ZSD,” Kim said.
Looking toward the future, the Kim-Bandsma team’s next step is to take this research into a preclinical ZSD model to test various therapeutics that could either increase autophagy or inhibit pexophagy.
