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

A cascade of NO in Alzheimer's disease One of the ill effects of the amyloid-β peptide that accumulates in Alzheimer's disease (AD) is the promotion of the production of nitric oxide (NO) and consequent nitrosylation of thiols in proteins such as dynamin-related protein 1 (Drp1), which can lead to loss of neuronal synapses. Nakamura et al. found that this S-nitrosylation occurs in an unusual way. They detected a series of transnitrosylation events in which an NO group is passed between at least three proteins. The deubiquinating enzyme Uch-L1 was S-nitrosylated in brains from human AD patients or in mouse models of AD. Uch-L1 could lead to S-nitrosylation of Drp1 after transferring the NO group to another enzyme, Cdk5 (cyclin-dependent kinase 5). The results implicate a mechanism in which unrelated enzymes might aberrantly function together to disrupt brain function. Science , this issue p. eaaw0843