By Michelle Jaffee
In aged mice and blood samples from Parkinson’s disease patients carrying an associated genetic mutation, researchers have shown that immune cells circulating outside of the brain are “exhausted,” or no longer function effectively. The findings reported Nov. 6 in Science Translational Medicine provide new understanding into possible influence of the immune system in Parkinson’s, as well as potential therapeutic targets.
A UF research team, led by MBI investigators Rebecca L. Wallings, Ph.D., and Malú GámezTansey, Ph.D., focused on the R1441C-LRRK2 genetic variant in the context of aging, as two factors known to increase risk of developing Parkinson’s are carrying an LRRK2 variant and having reached advanced age.
The research team assessed how the variant — a rarer mutation of the LRRK2 gene — affected immune responses and lysosomal function, or the digestive system of the cell, in peripheral immune cells in young versus old mice and male versus female. In addition, they tested peripheral blood mononuclear cells of three Parkinson’s patients carrying either the R1141C-LRRK2 or Y1699C-LRRK2 mutation; three R1141C-LRRK2 mutation carriers who did not yet manifest symptoms of Parkinson’s; and nine healthy controls. (The variant in this study is distinct from the G2019S-LRRK2 mutation, which is the largest contributor to hereditary forms of Parkinson’s.)
To characterize the effects of age, sex and genetic mutation on immune cell function, the research team used functional, immunological, and biochemical assays as well as RNA sequencing.
“In this study, we demonstrated that in aged female mice and patients with a Parkinson’s-associated genetic mutation, immune cells in the periphery were not hyperactive as once thought, but actually exhausted,” said Wallings, who led an international team of collaborators. “We demonstrated that immune cell exhaustion occurs in the periphery, but how this may contribute to disease onset and progression remains unknown.”
The findings help illuminate a possible role of the immune system in Parkinson’s as well as potential therapeutic pathways, she said.
“Over the last decade, researchers have attempted to unravel the role of inflammation in Parkinson’s, and a large amount of data have suggested that inflammation may be rampant and needs to be dampened in order to prevent or delay Parkinson’s and its progression,” she said. “However, much of these data were collected from young mice in preclinical models, and the role of an aging immune system has been largely ignored.”
The next step is to elucidate whether immune cell exhaustion is a factor in the death of neurons in Parkinson’s.
“If immune cell exhaustion contributes to risk for neurodegeneration, approaches such as immunotherapy, currently used in the cancer field, may be worth exploring to delay or prevent development or progression of Parkinson’s,” Tansey said.