Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer’s disease
Tomohiro Nakamura, Chang-ki Oh, Lujian Liao, Xu Zhang, Kevin Lopez, Daniel Gibbs, Amanda K. Deal, Henry Scott, Brian Spencer, Eliezer Masliah, Robert A. Rissman, John R. Yates, Stuart A. Lipton
Abstract
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.