NAD and NADPH in Neuronal Injury and Degeneration

The review focuses on novel targets recently identified in the mechanisms of neuronal death, and specifically in axonal degeneration. Depletion of NAD triggers various death pathways depending on the nature of the NAD degradation trigger. Wallerian degeneration (WD) of axons in the peripheral nervous system follows the specific mechanism activated by NMNAT2/SARM1 - "sarmoptosis", which is also observed in other tissues, and contributes to the chemotherapy-induced neurological effects. An allosteric inhibitor of the NADase activity of SARM1, SIR2501, has been recently approved by FDA for prevention of chemotherapy-induced peripheral neuropathy. Sarmoptosis cross-talks to apoptosis and ferroptosis in the injury-induced axonal degeneration of the central nervous system and, in particular, in spinal cord injury. NADPH plays opposing roles in the cell death. Ferroptosis suppressor protein 1 (FSP1), an NADPH-dependent enzyme, is the key actor generating ubiquinol Q10 to neutralize lipid peroxides. On the other hand, NOX4 activation results in ROS generation from NADPH. NADPH depletion through the polyol pathway activation diminishes antioxidant capacity of the cell and sends pro-death signal through the NADPH sensor in ER - ubiquitin ligase MARCHF6 (Membrane Associated Ring-CH-Type Finger 6). Under the conditions of low NADPH concentrations, MARCHF6 stabilizes pro-death proteins such as p53 and ferroptosis-fueling enzyme ACSL4 (Acyl-CoA synthetase long-chain family member 4). Under the conditions of high NADPH concentration, MARCHF6 ubiquitinates p53 and ACSL4 targeting them for the proteasomal degradation. Regulation of MARCHF6 activity is a promising target for intervention; however, no small molecules mimicking NADPH effect are currently available. In conclusion, the review discusses to what extent the existing NAD supplements could perform the role of targeted medicines.