Loss of nitric oxide in Alzheimer’s brains

Genes undergo extensive editing through a process called alternative splicing, which greatly increases the size of the functional genome—the working portion of our DNA that helps make each person unique. Put simply, a single gene can be edited in different ways to produce multiple sets of instructions. This helps explain why humans differ so significantly from fruit flies and mice, despite having a similar number of genes.

In a new study, published in Molecular Cell, researchers found that nitric oxide (NO)—a gas naturally produced in the body—can broadly regulate alternative splicing, dramatically altering how genes function.

“We further showed that nitric oxide levels are decreased in the brains of patients with Alzheimer’s disease, and that this loss of control over gene splicing correlates with worse clinical outcomes,” said the lead author. “In other words, lower nitric oxide levels lead to reduced gene-splicing activity, which is associated with increased plaque buildup and more rapid memory loss.”

The research team also found that specific enzymes remove nitric oxide from brain proteins that regulate splicing, creating a NO–deficient state. The findings suggest that targeting these enzymes could represent a new therapeutic strategy to restore NO levels in the brain and potentially treat Alzheimer’s disease.

The authors demonstrate that NO regulates alternative splicing (AS) and that S-nitrosylation of PTBP1, a central regulator of AS, can massively shift and contextually alter gene expression while further enriching the transcriptome for SNO sites.

PTBP1 S-nitrosylation changes RNA-binding domain conformation, RNA motif recognition, protein-RNA and protein-protein interactions, and intracellular trafficking to impact pathways for viral infection and neurodegeneration.

Levels of SNO-PTBP1 are reduced in mouse and human Alzheimer’s disease brains and correlate with adverse clinical outcomes.

“Interestingly, the Alzheimer’s field has long believed that nitric oxide levels were too high and contributed to the disease,” the author added. “This new discovery changes that paradigm.”

Next steps in this research will include studies in animals with new classes of enzyme inhibitors, which should restore nitric oxide in the brain and drive healthy splicing of genes.

https://www.cell.com/molecular-cell/fulltext/S1097-2765(26)00278-9

https://sciencemission.com/Nitric-oxide-drives-proteomic-diversity