Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease

Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer's disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.

Automated summary

This study describes mechanistically distinct enzymes that can mediate a series of redox reactions and lead to synapse loss in patients with Alzheimer's disease. These enzymes can form a separate network for aberrant transnitrosylation, which may not be effectively countered by natural selection in the post-reproductive period.