Genetic Signature in Parkinson’s-associated Immune Cells ID’d

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Some people with Parkinson’s disease have a characteristic genetic signature in a type of immune cell called memory T-cells, a new study suggests.

“Parkinson’s disease is not usually seen as an autoimmune disease, but all of our work points toward T cells having a role in the disease,” Cecilia Lindestam Arlehamn, PhD, a professor at La Jolla Institute for Immunology (LJI) and co-author of the study, said in a press release.

The study, “Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures,” was published in npj Parkinson’s Disease.

T-cells are immune cells equipped with specialized receptor proteins that can help them find and eliminate potential threats. A single T-cell has just one kind of receptor, which will specifically recognize that T-cell’s target — for example, a piece of an infectious virus or bacteria.

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When the T-cell’s receptor binds to its target, it prompts the cell to launch an inflammatory attack to fight the perceived threat. When this happens, the T-cell divides to make more identical T-cells, all with the same specific receptor. Most of these cells will fight the threat and die off once it’s destroyed, but some will stick around in the body’s tissues. These cells, called “memory” T-cells, are able to help launch a more potent immune response if the same threat is encountered later.

Parkinson’s disease is characterized by the abnormal buildup of clumps of the protein alpha-synuclein in brain cells. These irregular protein aggregates are thought to drive the disease’s progression. Recent research has suggested that as many as half of Parkinson’s patients have memory T-cells equipped with receptors that can recognize and launch an immune attack against the alpha-synuclein protein.

The role of these anti-alpha-synuclein memory T-cells in Parkinson’s pathogenesis — the biological process by which the disease develops and progresses — is poorly understood.

Researchers conducted genetic analyses on T-cells and other immune cells from 14 people with Parkinson’s who were positive for anti-alpha-synuclein memory T-cells, as well as 20 people with Parkinson’s who had no evidence of them. Nineteen people without Parkinson’s (or anti-alpha-synuclein memory T-cells) served as controls.

Comparing Parkinson’s patients to the controls generally found minimal differences in gene expression profiles — that is, which genes are “turned on or off.” But the patients with anti-alpha-synnuclein memory T-cells had more than 300 genes expressed differently with these disease-associated immune cells. Many of the genes were related to biological processes that have been shown to be involved in the pathogenesis of Parkinson’s.

“We show that memory T cells of [Parkinson’s] subjects with detectable [alpha-synuclein] responses possess specific [gene expression] signatures. … The specific genes and pathways identified that show significant enrichment of [gene expression] signatures previously associated with [Parkinson’s] include oxidative stress, oxidative phosphorylation, autophagy of mitochondria, chaperone-mediated autophagy, cholesterol metabolism, and inflammation,” the scientists wrote, adding that these processes “are known to be dysregulated in [Parkinson’s] and are widely thought to accelerate the progression of the disease.”

Interestingly, researchers found that LRRK2, a gene associated with familial Parkinson’s disease, was expressed in patients’ T-cells, mainly in those who were positive for anti-alpha-synuclein memory T-cells.

There also were genes that have never before been linked with Parkinson’s. “This finding suggests we found novel targets for potential therapeutics,” Alessandro Sette, a study co-author and professor at LJI, said.

Further study of these genes, and the dysregulation of T-cells in Parkinson’s more broadly, may pave the way towards identifying new therapeutic targets for the disease, the researchers suggested.

“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,” Sette said.