“Dark” Pathways of Protein Transnitrosylation Injure Synapses in Alzheimer’s Disease: Mechanism and Potential Treatment

抄録

Synaptic loss is the best neuropathological correlate to cognitive decline in Alzheimer’s disease (AD) and related dementias. Contributing factors include not only aggregated proteins such as amyloid-beta and tau, but also environmental factors such as air pollution and pesticides. These agents produce toxic stress from NOx (nitric oxide-related compounds), resulting in disruption of protein function via aberrant redox reactions on proteins, such as S-nitrosylation. Here, we describe distinct enzymes, a ubiquitin protein hydrolase (Uch-L1), a kinase (Cdk5), and a guanosine triphosphatase (Drp1), that act in concert to mediate a series of S-nitrosylation reactions from one to another. This non-canonical transnitrosylation cascade contributes to synaptic damage in AD. We show this series of reactions is kinetically and thermodynamically favored, resulting in mitochondrial fragmentation, bioenergetic compromise, and consequent synapse loss. We also develop a quantitative method based on Nernst equations for thermodynamic assessment of these redox reactions at steady state, as might be expected to occur in a chronic disease. This analysis reveals Gibbs free energies that are quite favorable for forward reaction through the transnitrosylation cascade. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network of aberrant transnitrosylation steps. Finally, we will present potential therapies to prevent the resulting loss of synapses and cognitive function due to these aberrant transnitrosylation reactions in AD brain.