New therapies could prevent T cells from attacking brain cells in Parkinson’s disease

Neurons Parkinson's disease

Parkinson’s disease is not usually thought of as an autoimmune disease. Image credit: Courtesy of Leterrier, NeuroCyto Lab, INP, Marseille, France

LJI scientists discover new targets for treating Parkinson’s disease.

Scientists at the La Jolla Institute for Immunology (LJI) have found that people with Parkinson’s disease have a unique “genetic signature” of the disease in their memory T cells. The scientists hope that targeting these genes can open the door to new treatments and diagnoses for Parkinson’s disease.

“Parkinson’s disease is not typically thought of as an autoimmune disease,” says LJI research assistant Professor Cecilia Lindestam Arlehamn, Ph.D. “But all of our work suggests that T cells play a role in the disease.”

“Now that we can see what these T cells are doing, we believe that intervention with antibody therapies could have an impact on disease progression, especially at an early stage,” adds LJI Professor Alessandro Sette, Dr. Biol .Sci., who directed the work with Lindestam Arlehamn.

This study was recently published in the journal npj Parkinson’s disease.

A changing perspective on Parkinson’s

Parkinson’s progresses when dopamine-producing neurons in the brain die. Unfortunately, scientists have been unable to pinpoint what causes this cell death — although they do have a clue: the doomed neurons contain clumps of a damaged protein called alpha-synuclein.

LJI research suggests these clumps could be the death knell for dopamine-producing neurons. Sette and Lindestam Arlehamn recently showed that people with Parkinson’s have T cells that target alpha-synuclein early 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 culprit behind many autoimmune diseases.

Researchers find unexpected drug targets

The new study offers a way to stop these T cells. The LJI team found that people with Parkinson’s disease have memory T cells with a very specific gene signature. These genes appear to be responsible for targeting alpha-synuclein and potentially causing persistent 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.

An important gene that is expressed in these T cells is LRRK2. This gene is linked to the genetic or familial nature of Parkinson’s disease. Neurons in many people with Parkinson’s express LRRK2, but the new study is the first to show this gene is expressed in T cells.

But many of the genes expressed in these T cells were completely unexpected and had not previously been linked to Parkinson’s disease. “This finding indicates that we have found new targets for potential therapeutics,” says Sette.

The researchers 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.[{” attribute=””>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.”

The path to new Parkinson’s therapies

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,” says Sette.

Reference: “Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures” 21 March 2022, npj Parkinson s Disease.
DOI: 10.1038/s41531-022-00282-2

Additional authors of the study, “Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures,” include first author Rekha Dhanwani, João Rodrigues Lima-Junior, Ashu Sethi, John Pham, Gregory Williams, April Frazier, Yaqian Xu, Amy W. Amara, David G. Standaert, Jennifer G. Goldman, Irene Litvan, Roy N. Alcalay, Bjoern Peters, and David Sulzer.

This research was supported by The Michael J. Fox Foundation for Parkinson’s Research, the Aligning Science Across Parkinson’s (ASAP) initiative (grant ASAP-000375), the National Institutes of Health (grants R01NS095435, T32AI125179, S10OD016262, and P50NS108675), and the JPB Foundation. New therapies could prevent T cells from attacking brain cells in Parkinson’s disease

Tom Vazquez

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