Abstract Body

We describe mechanistically-distinct enzymes, i.e., a ubiquitin protein hydrolase (Uch-L1), a kinase (Cdk5) and a guanosine triphosphatase (Drp1), which function in disparate biochemical pathways, that can also act in concert to mediate a series of redox reactions that contribute to neurodegenerative disorders. We show that each enzyme manifests a second, non-canonical function – transnitrosylation – triggering a pathological biochemical cascade in Alzheimer’s disease (AD). In this chemical redox reaction, NO (most likely in the form of nitrosonium cation or NO⁺) reacts with cysteine thiol (or more properly thiolate anion, R-S^-). The S-nitrosylation reaction mechanism involves thiolate anion, as a nucleophile, performing a reversible nucleophilic attack on the nitroso nitrogen to form an SNO-protein adduct. The resulting series of kinetically and thermodynamically-favored transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. Moreover, we develop a quantitative method based on a series of Nernst equations for thermodynamic assessment of the reactions at steady state, as might be expected to occur in a chronic disease. This analysis revealed Gibbs free energies that predict the spontaneous forward reaction of the transnitrosylation cascade. While other potential members of the cascade remain to be determined, this work shows that non-canonical pathways mediating a concerted cascade of aberrant transnitrosylation reactions can contribute to the pathogenesis of neurodegenerative disorders. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the post-reproductive period, so natural selection against such abnormal activity may be decreased.