New Model Demonstrates How Defects in RNA Splicing Contribute to Alzheimer’s Disease

Researchers at St. Jude Children’s Research Hospital in Memphis, TN have developed a new model for Alzheimer’s disease demonstrating how defects in the RNA splicing machinery of the cell contribute to the condition.

Alzheimer’s disease affects nearly six million people in the U.S. alone. Despite its prevalence, treatments to stop or reverse the disease’s effects on the brain as well as efficient models allowing scientists to study the disease in vivo are limited. Researchers at St. Jude Children’s Research Hospital say that they have now created a mouse model that more closely resembles the disease in humans than previous models.

Reporting in Nature Aging, the scientists were able to demonstrate that defects in RNA splicing contribute to the disease. Using their new mouse model, they deregulated the RNA splicing machinery in cells, observing consequent neurodegeneration.

RNA splicing is an essential step in the protein biosynthesis of cells, merging coding sequences of RNA together and removing non-coding ones. The researchers say that splicing is particularly important in the brain as the organ contains a variety of different cells requiring different proteins generated by different combinations of coding and non-coding sequences.

“Splicing machinery is so essential, and creating a model to study it in the lab was a real challenge. We were able to create a model of splicing dysfunction that occurred only in neurons. This model demonstrates splicing dysfunction that causes neuronal toxicity as well as cognitive impairment,” said Junmin Peng, professor at St. Jude Children’s Research Hospital, and co-author of the study in a press statement.

Previous research by Peng published in Proteomes, showed that a specific component of the RNA splicing machinery in the cell, called the U1 small nuclear riboprotein (snRNP), accumulates in the brain cells of Alzheimer’s patients. With the new mouse model, Peng and his team were able to show that the dysfunction of this component contributes to later neurodegeneration seen in patients suffering from the disease, paving the way for potential new treatments targeting the defective proteins involved in the splicing process.

“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.

The researchers also used their mouse model to study the combined effects of U1 snRNP aggregation in presence of ß-amyloid plaques, one of the hallmarks of Alzheimer’s disease. Upon combining the two factors in one model, the researchers were able to observe an accelerated cognitive decline.

“From the initial behavior to the cell biology and now to the molecular mechanism, we’ve characterized the potential contribution of RNA splicing machinery to neuron excitatory toxicity in Alzheimer’s disease,” Peng concluded in a press statement.