David Sulzer, PhD, on α-Synuclein Reactive T Cells and Preclinical Parkinson Disease

A new study published in Nature Communications suggests that α-synuclein (α-syn) reactive T cells may be present years before the diagnosis of motor Parkinson disease (PD) and are most abundant immediately after diagnosis. According to the authors of the study, these findings suggest “avenues of investigation into PD pathogenesis and potential early diagnosis.”

The researchers arrived at their conclusion after assessing the temporal relation between α-syn T cell reactivity and PD through a longitudinal case study, followed by an analysis of 2 independent cohorts and an additional analysis.

Findings from the longitudinal case study indicated that elevated α-syn-specific T cell responses were detectable before the diagnosis of motor PD was given, and subsequently declined. In the 2 independent cohorts, the researchers found that, in the association between T cell reactivity and early PD, α-syn-specific T cell responses appeared to be highest shortly after motor PD was diagnosed, and then decreased afterwards.

In an additional analysis, findings indicated that α-syn-specific T cell responses are significantly associated with age and lower equivalent dose of levodopa.

Neurology Consultant discussed these findings further with David Sulzer, PhD, professor of neurobiology (in Psychiatry, Neurology, and Pharmacology) at Columbia University Medical Center in New York, New York.

NEURO CON: What prompted you and your colleagues to assess the temporal relation between α-syn T cell reactivity and PD?

Dr Sulzer: One reason my colleagues and I conducted this study is because the first study we performed in 2017 showed many patients with a diagnosis of PD did not have T cell responses to α-syn. This could have been because the response is transitory, or some may have never had it at all. At this time, we suspect that both are true, but earlier cases of PD have far more T cell responses to α-syn.

NEURO CON: You and your colleagues found that, in 2 independent cohorts, α-syn-specific T cell responses were highest shortly after diagnosis of motor PD and then decreased, and that α-syn-specific T cell responses were significantly associated with age and lower levodopa equivalent dose. Do these findings yet have clinical significance?

Dr Sulzer: The clinical significance of these findings is not yet clear, but one possibility is that there is a high response during the period the dopamine neurons are dying, which is likely a small number of years before diagnosis and perhaps 3 years afterwards. The levadopa dose of course climbs during later stages, so this hypothesis is consistent with existing literature. One important question going forward will be whether this response is in some way responsible for cell death in PD, or if it is a consequence, or both.

NEURO CON: How do the findings from your study contribute to the existing literature on preclinical activity in PD?

Dr Sulzer: The findings from our present study show that the acquired immune system is certainly active prior to PD diagnosis.

NEURO CON: What key takeaways do you hope to leave with neurologists on this topic?

Dr Sulzer: We suspect, but do not have clear evidence, that increased inflammatory activity, even in the periphery as these cells are present in the blood, may play a role in pathogenesis of PD. Further research initiatives by our groups and others are currently underway. The findings from the present study may be helpful for PD diagnostics and demonstrating specific steps for new therapies.

NEURO CON: What is the next step in terms of future research in this area?

Dr Sulzer: There are quite a few areas of future research. Overall, longitudinal studies to confirm the responses we observed in our study will be important. We are currently developing mouse models for the many questions that cannot be directly addressed in humans, though we hope to follow up those findings with observations in humans.

—Christina Vogt

Reference:
Lindestam Arlehamn CS, Dhanwani R, Pham J, et al. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nat Commun. 2020;11:1875. doi:10.1038/s41467-020-15626-w