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Trash pickup problem
COLUMBIA, Mo.—When brain cells are functioning normally, mitochondria—the “powerhouses” of cells—generate the necessary energy to keep cells alive. When they become damaged and unable to make energy, mitochondria are sent to a portion of the cell called a lysosome to be repaired.
In the brains of Parkinson’s disease patients, mitochondria fail to move to the lysosomes, causing accumulations of damaged mitochondria that kill brain cells. The situation is what University of Missouri (MU) researcher Dr. Mark Hannink calls a “trash pickup problem,” as waste continues to be generated and not recycled or removed.
Hannink, a professor in the MU Department of Biochemistry and an investigator at the university’s Bond Life Sciences Center, has discovered a molecule that could aid mitochondrial recycling and keep brain cells alive. This could help to develop drugs to keep brain cells healthy in individuals with Parkinson’s disease, as he reported in “A conserved motif mediates both multimer formulation and allosteric activation of phosphoglycerate mutase 5,” recently published in the Journal of Biological Chemistry. Peter Tipton, MU professor of biochemistry, and graduate students Jordan M. Wilkins and Cyrus McConnell contributed to the research.
As Hannink explains, “Mitochondria eventually become damaged and no longer function properly, so the cell has a mechanism to recycle them, keeping them strong. If that recycling pathway doesn’t work, the defective mitochondria will build up and will disrupt cell physiology, ultimately causing that cell to die.”
Parkinson’s disease is the clearest example of this recycling failure.
“In early-onset Parkinson’s, mutated proteins ‘forget’ to recycle mitochondria, resulting in a buildup of toxic waste and early onset of the disease,” he says. “In our study, we found a peptide, or molecule, responsible for an alternative pathway that bypasses the mutant Parkinson’s proteins and allows mitochondrial recycling. We feel that this peptide could prove useful in fighting diseases in the brain.”
He adds, “The process that I am looking at is not repair of damaged mitochondria, but the removal/disposal/degradation of damaged mitochondria. This alternative pathway for mitochondrial recycling uses a protein called phosphoglycerate mutase family member 5 (PGAM5). A peptide acts as a ‘switch’ to cause the protein to create an alternate pathway.”
By regulating the protein with the peptide that Hannink discovered, it may be possible to restore mitochondrial recycling in neurons of patients with Parkinson’s, lessening the severity of the disease. He thinks that development of a drug based on the PGAM5 pathway could be useful in restoring mitochondrial recycling in certain cells, like neurons affected in Parkinson’s. while blocking this recycling pathway in other cells, like cancer cells.
“The PGAM5 protein would be regulated by an allosteric mechanism, in which its biological function would switch from activation of the PINK1/PARKIN pathway for removal of damaged mitochondria to the FUNDC1 pathway for removal of damaged mitochondria,” according to Hannink. “Peptides behave like drug molecules; any time you can identify a biological process that is regulated by a peptide, that peptide becomes a leading candidate in the search for small, drug-like molecules that will act the same way.”
For Parkinson’s disease, the goal is to find ways to repair the mitochondria recycling process. The next step of the research is to produce a drug molecule that can regulate the PGAM5 protein in cells, just as the peptide did in the experiments.
“We don’t know if this will reverse or stop Parkinson’s,” Hannink adds. “That will need to be tested in animal models, as the next step. But the idea is that by switching from the PINK1/PARKIN pathway, which is defective in some forms of familial Parkinson’s, to the FUNDC1 pathway, it might be possible to bypass the defective pathway and activate a compensatory pathway.”
Early-stage results of this research look promising, according to Hannink. If additional studies are successful within the next few years, MU officials will request authority from the federal government to begin human drug development. After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for Parkinson’s and other diseases.
“Commercial potential is sheer speculation at this point,” Hannink concludes.