To investigate the role of MitAP and mitochondrial-specific T cells in PD pathogenesis.

Parkinson’s disease (PD) is a neurodegenerative disorder linked to motor impairment and loss of dopaminergic neurons (DNs) in the substantia-nigra (SN). Although the underlying mechanisms are unclear, mitochondrial dysfunction and inflammation play key roles in PD pathogenesis. Remarkably, we reported that PINK1 and Parkin, two PD associated genes, are key regulators of immunity by repressing mitochondrial-antigen-presentation (MitAP). This pathway, triggered under stress conditions, is responsible for the establishment of autoreactive mitochondrial-specific T (mitoT) cells in PINK1-KO mice infected with gram-negative bacteria. Moreover, these mice develop PD-like symptoms and DNs degeneration. This strongly suggests that mitochondrial autoimmune mechanisms could participate in the aetiology of PD.

To directly assess the role of MitAP and mitoT-cells, we generated a new murine model of PD using adoptive transfer of activated mitoT-cells into WT and PINK1-KO mice. Frequency and level of activation of mitoT-cells was assessed using flow cytometry. We monitored the appearance of PD-like symptoms using pole test, grip test and actimetry, and then DNs degeneration and T-cell infiltration using immunostaining after perfusion.

Our findings show that mitochondrial specific T-cells are sufficient to induce PD-like symptoms and DNs degeneration in both WT and PINK1-KO mice. Indeed, as early as 21 days after transfer, mice show an increase in time-descent on the pole and slower total time movement in the open field test. Importantly, these motors symptoms are reversed after L-DOPA administration, strongly accrediting for an their affected dopaminergic projections.

We showed that even in the presence of PINK1 in DNs, once this mitochondrial autoimmunity is launched, DNs degeneration is achieved. Therefore, these data confirm the major role of PINK1 in the regulation of the immune system and suggest a poor role of this protein in the direct protection of DNs.