Once Parkinson’s disease (PD) symptoms begin, the damage is largely already done. But new research on the link between PD and the immune system suggests that T cells hint at PD progression long before major symptoms appear.
PD is known for uncontrolled movements caused by neurodegeneration, but the immune system also plays a key role in the progression of this devastating disease. T cells throughout the body trigger an inflammatory response to the aggregation of a protein called alpha-synuclein, a classic hallmark of PD that contributes to irreversible neuronal death.
In a new study published in npj Parkinson’s Disease, scientists reported that T cells hold clues to the progression of the disease through their PD-specific gene expression signatures, opening up paths for targeted intervention earlier in the progression of PD (1).
“It's a new avenue to target for therapeutics,” said Sonia George, a neuroscientist at the Van Andel Institute who is not affiliated with the study. “As there's no current disease-modifying treatments for PD — everything's just symptomatic — it's much needed.”
The phase before PD symptoms start is known as the “prodromal phase.” Patients may experience constipation, hyposmia, and sleep challenges, but they do not exhibit the characteristic PD movement-related symptoms. There are currently no identifiable biomarkers to indicate that a patient has PD during this prodromal phase.
Previously, the study authors led by neuroscientists Alessandro Sette and Cecilia Lindestam Arlehamn at La Jolla Institute for Immunology observed that Parkinson’s disease-associated T cell reactivity begins in the prodromal phase. The group also detected T cells that responded to alpha-synuclein in a PD patient years before the onset of motor symptoms (2).
In this new paper, the research team characterized the mRNA in PD patients’ T cells, which demonstrated autoimmune reactivity to alpha-synuclein. These T cells contained signatures for increased oxidative stress and inflammation compared to those from age-matched healthy controls, and they expressed certain PD-linked genes commonly seen in degenerating dopaminergic neurons
The researchers hope that some of the T cell gene signatures identified in the study may be used in the future as non-invasive biomarkers to identify PD before symptom onset by analyzing a blood sample. These signatures may also lead researchers to therapeutic targets.
“There is this growing awareness of an inflammatory and potentially a T cell response in neurodegenerative disease,” said Sette. “This inhibition of inflammation and potentially T cell responses early on could really have a profound effect in preventing the disease, or disease progression, or diagnosis.”
While the researchers only analyzed T cells from approximately fifty patients, they hope to further characterize the link between T cell alpha-synuclein reactivity and specific clinical manifestations of PD in more patients. Sette’s group would like to examine T cells present in the central nervous system, rather than circulating T cells found in patient blood.
George hopes that Sette’s group will examine T cell PD signatures over different time points of the disease. Sette is also interested in examining whether or not this T cell reactivity appears in other neurodegenerative diseases such as Alzheimer’s disease or amyotrophic lateral sclerosis.
“To take blood cells from patients to screen for their genetic signatures, I think that's the strength. It's something that can translate into therapies,” George said.
- Dhanwani, R. et al. Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures. npj Parkinson’s Dis 8, 30 (2022).
- Lindestam Arlehamn, C.S. et al. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nat Commun 11, 1875 (2020).