PINK1 deficiency rewires early immune responses in a mouse model of Parkinson's disease triggered by intestinal infection

Parkinson’s disease is characterized by a period of non-motor symptoms, including gastrointestinal dysfunction, preceding motor deficits by decades. This long prodrome is suggestive of peripheral immunity involvement in the initiation of disease. We previously developed a model system in PINK1 KO mice displaying PD-like motor symptoms at late stages following intestinal infections. Herein, we map the initiating immune events at the site of infection in this model. Using single-cell RNAseq, we demonstrate that peripheral myeloid cells are the earliest highly dysregulated immune cell type in PINK1 KO infected mice followed by an aberrant T cell response shortly after. We elucidate an increased propensity for antigen presentation mediated by myeloid-CD8+ T cell interaction. PINK1 KO activated myeloid cells acquire a proinflammatory profile inducing cytotoxic T cell responses. Together, our study provides the first evidence that PINK1 is a key regulator of immune functions in the gut underlying early PD-related disease mechanisms.