RNA Splicing Dysfunction in Alzheimer's Disease
RNA splicing is the process by which RNA is assembled from portions of a gene, joining exon sequences together while omitting intron sequences. Like all aspects of cellular biochemistry, RNA splicing runs awry with age in a variety of ways, and this is thought to lead to dysfunction in cells. Here, researchers dive into a very specific issue in RNA splicing that appears associated with Alzheimer's disease, though as always in this sort of research one has to ask whether the effect size is meaningful, and whether the animal models are decent reflections of what happens in humans. Mice do not naturally develop Alzheimer's, and so the models all are based on some assumptions about the important mechanisms; those assumptions may produce dementia in mice, but may or may not be relevant to the human condition.
Researchers previously 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, the 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.
The researchers created a novel mouse model of RNA splicing defects called N40K-Tg. The scientists observed basic neurodegeneration when they deregulated the splicing machinery, but they wanted to understand why that was the case. Inhibitory neuron activity prevents the brain from getting over-excited. If the inhibitory neuron activity is repressed, the neurons become more active, but it can cause toxicity. The researchers found a significant impact on synaptic proteins in the new mouse model, in particular the proteins involved in inhibitory neuron activity. "Excitatory toxicity is very important because it is already known in the Alzheimer's disease field. Even 20-30 years ago, people recognized that neurons become super excited, and now we find that the splicing machinery may be contributing to the excitatory toxicity observed in Alzheimer's patients."