New $6.2 million study seeks to define molecular linkages between aging and Parkinson's

A collaborative team between the University of Minnesota Medical School and Van Andel Institute (VAI) will soon begin a $6.2 million study that seeks to define the molecular linkages between aging and Parkinson's disease -- an approach for new treatment targets not yet explored by many researchers.

The group recently earned a three-year grant from the Aligning Science Across Parkinson's initiative, an international collaborative research effort partnering with The Michael J. Fox Foundation for Parkinson's Research to implement its funding.

The study will combine four labs -- two Medical School faculty labs led by Michael Lee, PhD, a professor in the Department of Neuroscience, and Laura Niedernhofer, PhD, a professor in the Department of Biochemistry, Molecular Biology and Biophysics; and two VAI Center for Neurodegenerative Science faculty labs led by Darren Moore, PhD, professor, and José Brás, PhD, associate professor. Lee, who is also with U of M Institute of Translational Neuroscience, is an expert in the cellular mechanisms of Parkinson's disease, which is the most common neurodegenerative movement disorder that affects more than six million people worldwide.

There are currently no treatments that can slow or stop the progression of the disease, but if you read the background on Parkinson's disease and risk factors, you will see that aging is the greatest risk factor, 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, Professor, Department of Neuroscience

Senescence, or the gradual deterioration of the body's functional characteristics over time, is the expertise of Niedernhofer, who is the director of the U of M Institute on the Biology of Aging and Metabolism.

"The National Institute on Aging has championed the geroscience idea that if old age is the number one risk factor for Parkinson's, Alzheimer's, cancer and other diseases, let's make drugs that target aging and not the individual diseases," Niedernhofer said. "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."

The team's preclinical studies will investigate three genes associated with late-onset Parkinson's disease -- LRRK2, VPS35 and α-synuclein, or SNCA -- to determine if increased senescence is associated with the disease and whether decreasing senescence can slow or stop the disease.

"Genetic predisposition is critical to defining a person's overall risk for Parkinson's, particularly when combined with other factors, such as age," Moore said. "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."

Brás will perform single-cell RNA sequencing to determine whether or not senescence occurs in human Parkinson's cases and if Parkinson's disease-associated genes impact senescence at a molecular level. This will help the team identify stronger mechanistic connections between their animal models of the disease and human Parkinson's.

"Although senescence has been investigated in various contexts for many years, few studies have looked at this event in Parkinson's disease," Brás said. "This collaborative project will be the first time that we will be able to take a comprehensive view of the role of senescence in Parkinson's using state-of-the-art approaches and integrating troves of genomic data from models and humans."

If the team discovers that senescence is linked to the progression of Parkinson's disease, their findings could lead to an immediate clinical trial using senolytics as a form of treatment for the disease. These drugs, already under study in many other Phase II clinical trials, are used to clear aging cells, and in preclinical studies, have proven effective in delaying, preventing or alleviating frailty and many other aging-related diseases.