Research

Nakamura Lab: In-depth

The global prevalence of neurodegenerative disorders, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), is increasing with extended life expectancy. Although precise cellular and molecular mechanisms underlying neurodegeneration still remain enigmatic, key features of these devastating disorders have been identified, including elevated oxidative/nitrosative stress, mitochondrial dysfunction, protein misfolding/aggregation, synapse loss, and decreased neuronal survival. In particular, aberrant S-nitrosylation reactions can occur with aging or environmental toxins that generate excessive NO, affecting protein misfolding, mitochondrial fragmentation, synaptic function, apoptosis or autophagy. Our research discovered how aberrantly S-nitrosylated proteins play a crucial role in the pathogenesis of neurodegenerative diseases, including AD and PD. Our findings provided insight into the pathophysiological role of aberrant S-nitrosylation pathways that enhance our understanding of molecular mechanisms leading to neurodegenerative diseases and point to potential therapeutic interventions.

A growing literature suggests that over 1000 proteins are S-nitrosylated in cell systems. However, the mechanism by which specific protein S-nitrosylation occurs in cell signaling pathways is less well investigated. Interestingly, the recent discovery by our groups of protein-protein transnitrosylation reactions (transfer of an NO group from one protein to another) has revealed a unique mechanism whereby NO can S-nitrosylate a particular set of protein thiols, and represents a major class of nitrosylating/denitrosylating enzymes in mammalian systems. Thus, these studies opened a new research field in the area and implicated that elucidation of additional transnitrosylation cascades will further our understanding of NO-mediated signaling pathways leading to neurodegenerative conditions.