Could immune system ‘exhaustion’ contribute to Parkinson’s?
Scientist using grant to take fresh look at disease causes, therapy approaches
As people age, the immune system ages with them, becoming more sluggish and ineffective — a change that could contribute to Parkinson’s disease, Rebecca Wallings, a 2024 Parkinson’s Foundation Launch Award grant recipient, suggests.
“As you age … your immune cells can become exhausted … slow, sluggish, and not able to resolve inflammation like they used to,” Wallings, a senior postdoctoral fellow at the University of Florida’s Center for Translational Research in Neurodegenerative Disease, said in a foundation “advancing research” blog post and report. “We think it is that accumulation of exhausted immune cells that are potentially driving degeneration in the brain.”
Her research focus, which earned the scientist this four-year, two-part award, is on the mechanisms contributing to immune cell exhaustion, the diminished ability of immune cells to regulate immune responses with age, in the peripheral immune system. The peripheral system covers all immune cells outside the brain and spinal cord, which make up the central nervous system.
“We quite often think of Parkinson’s disease as a disorder that affects primarily the brain,” Wallings said in an accompanying video. But “it’s been relatively well understood in the last five or 10 years that the peripheral immune system might be contributing to the disease.”
Scientist 1 of 3 winners of 2024 Parkinson’s Foundation Launch Award
Her awarded project, titled “Investigating the effects of LRRK2 mutations in immune exhaustion,” aims to determine how an aging immune system contributes to Parkinson’s and the neurodegeneration, or loss of nerve cells, that underlies the disease.
Parkinson’s is caused by the dysfunction and loss of dopaminergic neurons, the nerve cells responsible for producing the chemical messenger dopamine. This results in impaired dopamine signaling in the brain, ultimately leading to disease symptoms.
Exactly what drives neuronal damage is not fully understood, but inflammation long has been considered to play a role. As such, scientists sought to address inflammation by dampening the immune system. Wallings, in her work, questions that approach.
“For the longest time the field thought that inflammation in Parkinson’s was something that was rampant, that there was too much of it. It was something that needed to be decreased to alleviate symptoms,” she said. “But my research has shown that the complete opposite might be happening. Instead of dampening an already suppressed immune system, we should try to rejuvenate it to make it work more efficiently.”
Wallings, particularly, is looking at mitochondrial dysfunction as an underlying mechanism in immune cell exhaustion. Mitochondria are cellular structures crucial for energy production in cells, and work she has done in preclinical disease models pointed to problems in the workings of mitochondria — including those linked to Parkinson’s-related gene mutations.
“As immune cells age, their mitochondria don’t work as efficiently, and that is causing the exhaustion,” Wallings said. “If we can potentially fix the mitochondria and allow the immune cells to have good, well functioning energy, perhaps we can reverse that exhaustion.”
Potential to repair or revitalize immune system as way of treating disease
Previously, Wallings showed that mutations in the LRRK2 gene were associated with age-related immune cell exhaustion and a poorer immune system response to insults. LRRK2 mutations also are considered to be a genetic risk of Parkinson’s.
Working in cell models from Parkinson’s patients and healthy adults, as well as in mouse disease models, Wallings plans to test whether approaches for repairing or rejuvenating mitochondria in the immune system strengthen that system, and could help to treat or prevent the disease.
Wallings is among three young investigators working in Parkinson’s selected for a Launch Award, with a grant total of $1.2 million, by the Parkinson’s Foundation last year.
Her grant will go toward establishing her own lab, with its independent focus on the role of immune cells in the disease.
“I want to have my own lab where I’m kind of calling the shots, with the focus being immune cell exhaustion. … Foundations like the Parkinson’s Foundation are starting to invest and fund in researchers who are thinking outside the box, or outside the brain,” she said.
“The field is changing and we are starting to go these other routes, where we are thinking about the role of the gut, the role of infection, the role of environmental exposures. … Now people are starting to pay attention to kind of the ‘whole systems approach’ to Parkinson’s disease, and I think it’s those approaches that will make real tangible differences,” Wallings said.
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