Aberrant Protein S‐Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases
Year: 2026
Type: article
Abstract: Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes.
Source: Journal of Neurochemistry
DOI: 10.1111/jnc.70365
Authors: Yubo Wang, Stuart A. Lipton
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Aberrant protein S-nitrosylation mediates Gene-Environment Interactions in AD/ADRD, G3194750708, G3508999709, Novel Proteomics Approach to HIV-Associated Neurocognitive Disorder & Drug Abuse, G3856297178, Dynamic Interactions of the S-Nitrosoproteome in Type 2 Diabetes/Metabolic Syndrome and Alzheimer’s Disease, Pro-Electrophilic Drugs PEDs for Alzheimer's Disease, G6366408802, S-Nitrosylation-Induced Posttranslational Modification and Aberrant Cell Signaling in Sporadic Alzheimer's Disease, G7997691507, G9000081447, G9000206208, G9000305845
OpenAlex ID: W7127600944