Pink Light on Mitochondria in Autoimmunity and Parkinson Disease

Abstract

Mitochondrial dysfunction and T cell autoimmunity have been independently implicated in Parkinson disease pathogenesis. In a recent publication in Cell, Matheoud et al. (2016) link them by describing a new mechanism, activated in familial forms of Parkinson disease, in which mitochondrial proteins are processed for recognition by CD8+ T cells.

FIGURE 1. Mitochondrial antigen presentation (MitAP) and inhibition by PINK1 and Parkin

Mitochondria derived vesicles (MDVs) arise from mitochondrial buds in a process requiring RAB9 GTPase and SNX9. RAB7 likely promotes MDV fusion with lysosomes/multivesicular bodies (MVBs) to allow processing of MDV cargo antigens and MitAP. PINK1 and Parkin normally antagonize MitAP, but their absence in familial forms of Parkinson Disease (PD) promotes MitAP, leading to the development of mitochondrial antigen-reactive CD8+ T cells. Dopaminergic neurons upregulate MHC-I molecules in inflammatory conditions, and might activate MitAP in PINK1- or Parkin-deficient PD. Reactive CD8+ T cells might cross the blood brain-barrier, bind to MHC-I:mitochondrial peptide complexes and kill these neurons, leading to PD pathology.