It’s as if your recycling man quit his job and never came back.
Bags pile up to unexpected heights as waste continues to be generated and brought out to the curb. Day after day, the waste builds up as no one comes to pick them up.
For individuals with Parkinson’s disease, an accumulation of waste causes specific brain cells to die. The result is the onset of the disease.
But, instead of aluminum cans, plastics and paper, the waste that builds up in the brain cells of individuals with Parkinson’s is damaged mitochondria. Mitochondria are the cellular components that generate energy needed to keep cells alive.
When mitochondria is damaged and is no longer capable of making energy, it must be sent to the recycling center of a cell (called the lysosome).
Mark Hannink, a scientist at the Bond Life Sciences Center and professor of biochemistry at the University of Missouri, is peeling away the layers of this onion, one at a time.
His new research on a novel protein called PGAM5 (phosphoglycerate mutase family member 5) is pointing the way to finding a drug that can treat the disease.
Mitochondria suffer “wear and tear,” just like old cars
Mitochondria are endlessly helpful to a cell.
These powerhouses produce energy for a cell, control the cell division cycle and help regulate synapses. However, the mitochondrial proteins that produce energy eventually become damaged and no longer function properly.
“That’s part of the normal life cycle of mitochondria,” Hannink said. “Just like when the motor in an old car gives out due to wear and tear, that motor needs to be taken out and sent to the scrap dealer to be recycled and a new motor needs to be put in the car to keep it running.”
When mitochondria wear out they need to be sent to “recycling.”
“If that recycling pathway doesn’t work, the defective mitochondria will build up and will disrupt cell physiology, ultimately causing that cell to die” Hannink said.
Parkinson’s Disease is the clearest example of this recycling failure.
In early onset Parkinson’s, mutated proteins “forget” to take damaged mitochondria to the recycling center, resulting in build-up of toxic waste and, eventually, early onset of the disease.
“If the recycling mechanism isn’t functioning properly, those neurons die,” Hannink said.
Peptides behave like drug molecules
Hannink recently published research on the PGAM5 pathway in the Journal of Biological Chemistry along with MU graduate students Jordan M. Wilkins and Cyrus McConnell and fellow Biochemistry faculty member, Peter Tipton.
While its basic nature hides it from the view from the general public, this research takes a large step in the science of Parkinson’s disease.
Beyond defining the regulation of a pathway largely unstudied, their work discovered that a peptide regulates the pathway. Importantly, this peptide is able to alter the activity of the PGAM5 protein and stimulate an alternative recycling pathway for mitochondria.
Peptides are a clear signpost on a path toward drug development.
“Any time you can identify a biological process that is regulated by a peptide, that peptide becomes a lead candidate in the search for small, drug-like molecules that will act the same way,” Hannink said.
For Parkinson’s Disease, the goal is to find ways to repair the mitochondria recycling process.
“We propose that, by regulating PGAM5, it may be possible to restore mitochondrial quality control to dopaminergic neurons of patients with Parkinson’s and lessen the severity of the disease,” Hannink said.
While Hannink’s findings are exciting, there are also nuances to consider.
His research focuses on familial Parkinson’s disease, and it remains unknown whether sporadic Parkinson’s is also due to a defective mitochondrial recycling pathway. Sporadic Parkinson’s accounts for the vast majority of cases and typically affects older people.
It’s not clear if the PGAM5 pathway is also defective in those cases, Hannink said.
The next step of his research is to identify a small molecule that can regulate the PGAM5 protein in cells, just as the peptide did in his test-tube exper