Targeting the T-cell response as a novel therapeutic strategy for Parkinson's disease

Parkinson's disease (PD) is characterized by the loss of dopamine-producing neurons and abnormal alpha-synuclein buildup, leading to motor and cognitive symptoms. CD4+ T-cells play a crucial role in PD, influencing disease progression differently across preclinical models. While they aid zebrafish regeneration, they hinder brain recovery in mice. In humans, CD8+ T-cells increase more significantly than CD4+ in PD cases, and their infiltration precedes alpha-synuclein aggregation and neuronal death, suggesting their relevance in disease onset.Here, we set out to uncover which T-cell subsets regulate brain repair mechanisms as a rationale for new PD therapies. We employed zebrafish and mice and damaged their dopaminergic neurons using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated zebrafish exhibited neurodegeneration and T-cell infiltration. Once tissue regenerated, T-cells became sporadic, suggesting a primary role of T-cells during neurodegeneration. MPTP-induced degeneration in mice resulted in a pronounced recruitment of CD8+ T-cells. In contrast, genetically modified mice overexpressing alpha-synuclein exhibited CD4+ T-cell clustering, indicating that different pathological features of PD affect T-cell infiltration differently. Additionally, we analyzed post-mortem samples from patients with PD. T-cells were recruited in PD-affected tissue with scarce presence in healthy brains. The number of T-cells significantly correlated with PD-associated hallmarks, indicating a potential involvement during neurodegeneration and alpha-synuclein accumulation.Overall, our study indicates that CD8+ and CD4+ T-cells play varying roles in PD-related neurodegeneration, depending on the model and pathological features. These findings shed light on the complex interplay between T-cells and PD, offering insights for developing therapies in both preclinical models and human cases.