by Buck Institute

A Potential New Therapeutic Approach for Parkinson’s Disease

Clearing senescent astrocytes prevents Parkinson’s in mouse model of sporadic disease.

NOVATO, Calif. — Systemic clearing of senescent astrocytes prevents Parkinson’s neuropathology and associated symptoms in a mouse model of sporadic disease, the type implicated in 95 percent of human cases. Publishing in Cell Reports, researchers in the Andersen lab at the Buck Institute provide a new potential therapeutic avenue for Parkinson’s disease, an incurable, progressive neurological disorder that affects up to 1 million Americans, robbing them of the ability to control movement.

Senescent cells, which stop dividing in response to stress, secrete deleterious factors that cause tissue damage and lead to chronic inflammation. In this study, senescence was triggered by exposure to the pesticide paraquat, a neurotoxin that in 2011 was formally linked to the development of Parkinson’s disease in farmworkers.

Julie K. Andersen, PhD, Professor

“While senescence has been implicated in Parkinson’s and other neurodegenerative diseases, we believe this is the first time that clearing the inflammatory cells prevented symptoms from developing in a live mammal,” said Julie K. Andersen, PhD, Buck Institute professor and senior author on the paper. “We hope the fact that we were able to do this in a sporadic, rather than genetic, model of Parkinson’s highlights its relevance as a potential new way to tackle the most prevalent form of the disease.”

This research is unusual given that it focuses on senescence in astrocytes, so called “helper” cells that perform a variety of tasks, from axon guidance and synaptic support to control of the blood-brain barrier and blood flow. Even though astrocytes are the most numerous cell type within the central nervous system, Andersen says they have been underappreciated “stepchildren” in most basic neuroscience research. She says the vast majority of Parkinson’s research has focused on toxicity that directly affects specific neurons implicated in the disease, “but no one has come up with an effective treatment based on that approach. This research suggests that senescent astrocytes may contribute to the development of the disease, and we’re excited to explore this avenue.”

The research, led by adjunct faculty Shankar Chinta, PhD, and postdoctoral fellow Georgia Woods, PhD, showed that postmortem tissue from patients with Parkinson’s displays increased astrocytic senescence and that cultured human astrocytes exposed to paraquat become senescent, as well.

The mice used in this research were six months old, which is roughly equivalent to a 34-year-old human. Andersen’s lab hopes to study the impact of astrocytic senescence in mice at varying stages of lifespan to see if Parkinson’s can be reversed in addition to being prevented. “Chronic inflammation fueled by senescence drives many age-related diseases, and it’s quite possible that Parkinson’s is among them,” says Andersen, who adds that astrocytic inflammation may play a role in other neurodegenerative diseases such as Alzheimer’s. “This model gives us a way to expand how we look at and potentially treat a range of maladies,” she says.

There is a desperate need for treatments for Parkinson’s. An estimated 7 to 10 million people are living with the disease worldwide. In addition to resting tremor and difficulty with walking and balance, Parkinson’s also leads to cognitive decline and depression, with symptoms becoming more severe as the disease progresses. About 5 percent of cases are caused by genetics. The remainder are believed to be caused by a combination of both genetic and environmental factors, such as family history, genetic mutations, drinking well water, and exposure to pesticides or metal.

This research was covered in The Scientist.

Citation: Chinta, S. J., Woods, G., Demaria, M., Rane, A., Zou, Y., McQuade, A., . . . and Andersen, J. K. (2018). Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson's disease. Cell Reports, 22(4), 930–940. DOI: 10.1016/j.celrep.2017.12.092

Other Buck researchers involved in the study include Shankar J. Chinta, Georgia Woods, Marco Demaria, Anand Rane, Ying Zou, Amanda McQuade, Subramanian Rajagopalan, Chandani Limbad, David T. Madden, and Judith Campisi.

The work was supported by grants from the National Institutes of Health (AG009909, T32-AG000266), the Michael J. Fox Foundation, the Ellison Medical Foundation Senior Scholar in Aging award, a training grant from the California Institute for Regenerative Medicine, the American-Italian Cancer Foundation, and the Buck Institute Impact Circle.

Science is showing that while chronological aging is inevitable, biological aging is malleable. There's a part of it that you can fight, and we are getting closer and closer to winning that fight.

Eric Verdin, MD, Buck Institute President and CEO

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