Abstract:

Granted that the “oxidation-through-lifetime” hypothesis was correct, what consequences would emerge for future neuroprotective strategies? Most basically, humans and mice are different, even with respect to such fundamental aspects of redox homeostasis asprotein carbonyl formation. In humans, cytosolic protein oxidation appears to be much less of a problem than damage to membrane proteins, which might clearly account for the failure in humans of the exclusively aqueous double-sulfocompound NXY-059 that had been quite efficacious in rodents. Gyrencephalic animal models might provide some solution to avoid the rodent-human gap, as also mentioned in the STAIR recommendations for stroke, but it is clear that those are very much demanding. What could one still achieve in mice? Clearly, the study of protein turnover should provide significant insight. Moreover, the identification of proteins with very high baseline oxidation levels, or the search for proteins that are selectively degraded after an insult or in a disease might be more rewarding than the everlasting search for further proteins whose steady-state levels of oxidation are somewhat higher in a disease: the latter proteins might just reflect a selection of proteins whose oxidation is unusually well tolerated by the cell, such that it postpones their degradation to a later point. In the end, the study of protein oxidation in the dynamic context of turnover and site-specific degradation in the brain seems crucial, if only so for the realization of better treatment options for the primary proteolytic failure diseases.