Bidirectional Interaction Between IL and 17A/IL-17RA Pathway Dysregulation and Α-Synuclein in the Pathogenesis of Parkinson’s Disease

Parkinson's disease (PD) pathogenesis is characterized by alpha-synuclein (alpha-syn) pathology, which is influenced by various factors such as neuroinflammation and senescence. Increasing evidence has suggested a pivotal role for Interleukin-17A(IL-17A) and Interleukin-17 Receptor A (IL-17RA) in PD, yet the trigger and impact of IL-17A/IL17RA activation in PD remains elusive. This study observed an age-related increase in IL-17A and IL-17RA in the human central nervous system, accompanied by increased alpha-syn and senescence biomarkers. Interestingly, both levels of IL-17A and IL-17RA in PD patients were significantly elevated compared to age-matched controls, wherein the IL-17A was mainly present in neurons. This abnormal neuronal IL-17A activation in the PD brain was recapitulated in alpha-syn mouse models. Correspondingly, administration of recombinant IL-17A exacerbated pathological alpha-syn in both neuron and mouse models. Furthermore, IL-17A/IL-17RA pathway interventions via blocking antibody or shRNA-mediated knockdown can mitigate the effects of pathological alpha-syn. This study reveals an interplay between dysregulation of the IL-17A/IL-17RA pathway and alpha-syn, suggesting that regulating the IL-17A/IL-17RA pathway could modify PD progression by disrupting the detrimental cycle.