Primate differential redoxome (PDR) – A paradigm for understanding neurodegenerative diseases

Despite different phenotypic manifestations, mounting evidence points to similarities in the molecular basis of major neurodegenerative diseases (ND). CNS has evolved to be robust against hazard of ROS, a common perturbation aerobic organisms are confronted with. The trade-off of robustness is system's fragility against rare and unexpected perturbations. Identifying the points of CNS fragility is key for understanding etiology of ND. We postulated that the ‘primate differential redoxome’ (PDR), an assembly of proteins that contain cysteine residues present only in the primate orthologues of mammals, is likely to associate with an added level of regulatory functionalities that enhanced CNS robustness against ROS and facilitated evolution. The PDR contains multiple deterministic and susceptibility factors of major ND, which cluster to form coordinated redox networks regulating various cellular processes. The PDR analysis revealed a potential CNS fragility point, which appears to associates with a non-redundant PINK1-PRKN-SQSTM1(p62) axis coordinating protein homeostasis and mitophagy.