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

Abstract

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.

The Role of Protein Persulfidation in Brain Aging and Neurodegeneration

“…Neurodegenerative diseases (ND) are characterized by a progressive damage to neurons that results in compromised cognitive and/or motor functions. One of the common characteristics of ND is its age-dependency; for instance both Alzheimer's and Parkinson's diseases affect 10 and 2% of the elderly population in the USA, respectively (Liu et al, 2017 ; Venkatachalam et al, 2020 ). Recent analysis of primate proteomes with different ND found that 16% of the analyzed proteins contained one or more cysteines unique to primates.…”

“…Structural analysis of these proteins revealed that in a vast majority of the cases, these unique cysteine residues were surface-exposed, making them more susceptible to oxidation. The authors identified this group of proteins as “primate differential redoxome” showing that it contains multiple deterministic and susceptibility factors of major ND (Venkatachalam et al, 2020 ). In the light of the above-mentioned facts that protein persulfidation acts as a general protective mechanism, it is tempting to speculate that there might be a causal link between aging-induced P-SSH decline and ND.…”