Researchers at the La Jolla Institute for Immunology (LJI) say they have found that people with Parkinson’s disease have a clear “genetic signature” of the disease in their memory T cells. The scientists, who published their study “Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures” in npj Parkinson’s Disease, hope that targeting these genes may open the door to new Parkinson’s treatments and diagnostics.
“Parkinson’s disease (PD) is a multi-stage neurodegenerative disorder with largely unknown etiology. Recent findings have identified PD-associated autoimmune features including roles for T cells. To further characterize the role of T cells in PD, we performed RNA sequencing on PBMC and peripheral CD4 and CD8 memory T cell subsets derived from PD patients and age-matched healthy controls,” write the investigators.
“When the groups were stratified by their T cell responsiveness to alpha-synuclein (α-syn) as a proxy for an ongoing inflammatory autoimmune response, the study revealed a broad differential gene expression profile in memory T cell subsets and a specific PD associated gene signature. We identified significant enrichment of transcriptomic signatures previously associated with PD, including for oxidative stress, phosphorylation, autophagy of mitochondria, cholesterol metabolism and inflammation, and the chemokine signaling proteins CX3CR1, CCR5, and CCR1.
“In addition, we identified genes in these peripheral cells that have previously been shown to be involved in PD pathogenesis and expressed in neurons, such as LRRK2, LAMP3, and aquaporin. Together, these findings suggest that features of circulating T cells with α-syn-specific responses in PD patients provide insights into the interactive processes that occur during PD pathogenesis and suggest potential intervention targets.”
“Parkinson’s disease is not usually seen as an autoimmune disease,” says LJI Research Assistant Professor Cecilia Lindestam Arlehamn, PhD. “But all of our work points toward T cells having a role in the disease.”
“Now that we can see what these T cells are doing, we think intervening with antibody therapies could have an impact on the disease progression, especially early on,” adds LJI Professor Alessandro Sette, D. BioL. Sci., who led the work with Lindestam Arlehamn.
Parkinson’s progresses as dopamine-producing neurons in the brain die. Unfortunately, scientists have been unable to pinpoint what causes this cell death—though they do have a clue: The doomed neurons contain clumps of a damaged protein called alpha-synuclein.
LJI research suggests these clumps may ultimately silence dopamine-producing neurons. Sette and Lindestam Arlehamn recently showed that people with Parkinson’s have T cells that target alpha-synuclein early on in Parkinson’s disease. Self-reactive T cells can damage the body’s own cells, including neurons. In fact, self-reactive T cells are the culprits behind many autoimmune diseases.
Unexpected drug targets found
The new study offers a potential way to stop these T cells in their tracks. The LJI team found that people with Parkinson’s disease have memory T cells with a specific gene signature. These genes appear responsible for targeting alpha-synuclein and potentially causing ongoing inflammation in cases of Parkinson’s.
“Identifying these genes will make it possible to see which patients have T cells that respond to alpha-synuclein and which do not,” says Lindestam Arlehamn.
One important gene expressed in these T cells is LRRK2. This gene is associated with the genetic, or familial, type of Parkinson’s disease. Neurons in many people with Parkinson’s express LRRK2, but the new study is the first to show this gene expressed in T cells.
But many of the genes expressed in these T cells were completely unexpected and not previously linked to Parkinson’s disease. “This finding suggests we found novel targets for potential therapeutics,” says Sette.
The scientists found these genes expressed in blood samples collected at LJI’s John and Susan Major Center for Clinical Investigation and by study collaborators at UC San Diego, Columbia University Irving Medical Center, and the University of Alabama at Birmingham.
“We couldn’t have done any of this work without local blood donors and the instrumental work of our Center for Clinical Investigation,” says Lindestam Arlehamn. “Everyone ships their blood samples to us, and the LJI Center for Clinical Investigation processes them.”
Going forward, Lindestam Arlehamn and her collaborators plan to study post-mortem brain samples. This work will confirm whether the same self-reactive T cells found in blood also target neurons in people with Parkinson’s. The team also wants to look for other targets, called antigens, that might be recognized by T cells in individuals with Parkinson’s disease.
To translate this work to new therapies, it will be important for scientists to study how they can activate or inhibit different genes at different stages of Parkinson’s progression.
“We have many avenues now for future research,” notes Sette.
