Researchers have puzzled over the neurodegenerative disorder Alzheimer’s disease for decades, but treatments to stop or reverse the disease’s effects on the brain have remained elusive. Scientists at St. Jude Children’s Research Hospital recently added an important piece to the puzzle by creating a mouse model that more closely resembles the disease in humans than previous models. The findings appeared today in Nature Aging.

The researchers used their new model to discover how defects in RNA splicing contribute to neurodegeneration in Alzheimer’s disease. RNA splicing is a process that removes non-coding genetic sequences and joins protein-coding sequences together.

“RNA splicing is an essential step between transcription and translation,” said corresponding author Junmin Peng, Ph.D., St. Jude Departments of Structural Biology and Developmental Neurobiology and the Center for Proteomics and Metabolomics, who led the research. “It is particularly important in the brain because we know the brain has more cellular diversity than any other organs in the body and splicing is believed to be an important process for generating protein diversity.”

Previous work by Peng and others revealed that a specific component of the RNA splicing machinery, called the U1 small nuclear ribonucleoprotein (snRNP), creates aggregates in the brains of individuals with Alzheimer’s. The U1 snRNP complex is essential in RNA splicing.

Now, Peng and his team have demonstrated that the dysfunction of the U1 snRNP contributes to neurodegeneration, opening new avenues of research for Alzheimer’s treatment. The study found that RNA splicing dysfunction due to U1 snRNP pathology helps cause neurodegeneration.

“Our previous work showed that the U1 snRNP is a type of aggregate in the brain that forms tangle-like structures — but that is just descriptive, we didn’t understand the mechanisms that link this pathology to the disease phenotype until now,” Peng said.

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