The three-year grant, funded by the Michael J. Fox Foundation, was given to a collaborative team of researchers from the University of Minnesota Medical School and the Van Andel Institute in Grand Rapids, Michigan.
During the natural process of aging, the main risk factor for both sporadic and genetic forms of Parkinson’s, humans accumulate senescent cells within their tissues. Cellular senescence refers to when cells cease to divide and grow, and can no longer regenerate tissues.
Cellular senescence is important in both embryonic development and wound healing and plays a role in preventing the development of certain cancers by guarding against unrestricted growth of damaged cells.
However, senescent cells tend to emit chemicals into their environment that can damage surrounding cells. In addition to accumulating in healthy older tissue, senescent cells can abnormally accumulate in disease states.
“Aging is the greatest risk factor [in Parkinson’s], yet no one knows why. For the next three years, we will be studying cellular senescence to see whether or not it is participating in the neurodegeneration seen in the Parkinson’s disease models,” Michael Lee, PhD, a professor at the University of Minnesota’s Institute of Translational Neuroscience, said in a press release.
In their study, the researchers will begin by using novel mouse models to test if premature senescence causes disease in specific cell types. They then will combine mouse models of senescence and familial Parkinson’s to examine if senescence plays a role in the disease linked to mutations in the SNCA, LRRK2, and VPS35 genes.
Specifically, the team wants to determine if increased senescence is associated with Parkinson’s and whether decreasing senescence can slow or stop the disease.
“SNCA, LRRK2 and VPS35 have demonstrated genetic links to Parkinson’s, particularly later in life, and as such, offer promising opportunities for the development of new treatments designed to target the root causes of the disease,” said Darren Moore, PhD, a professor at the Van Andel’s Center for Neurodegenerative Science.
Researchers will also perform a gene expression analysis of Parkinson’s brains and mouse brains at a single-cell level to gain high-resolution insights about cellular processes that link aging and Parkinson’s. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.
If a link between senescence and Parkinson’s progression is found, this work could support the use of senolytics — medicines that selectively kill senescent cells — as new disease-modifying therapies for Parkinson’s.
Because senolytics are already in Phase 2 clinical trials for other indications, the researchers believe they could rapidly enter the testing stage for Parkinson’s.
“Senescent cells are one of those aging targets that is quite druggable, and it offers a brand-new approach in treating Parkinson’s disease that no one has tried before,” said Laura Niedernhofer, PhD, a professor in the Department of Biochemistry, Molecular Biology and Biophysics at the University of Minnesota.
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