Mouse model shows how RNA splicing defects contribute to neurodegeneration in Alzheimer's disease

Mouse model shows how RNA splicing defects contribute to neurodegeneration in Alzheimer's disease

Researchers have pondered the neurodegenerative disease Alzheimer's 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 results 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 in 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 that the brain has greater cell diversity than any other organ in the body, and splicing is thought to be an important process for generating protein diversity.”

Previous work by Peng showed that a specific component of the RNA splicing machinery, U1 small nuclear ribonucleoprotein (snRNP), forms aggregates in the brains of people with Alzheimer's disease. The U1-snRNP complex is essential in RNA splicing.

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

Our previous work showed that the U1 snRNP is a type of aggregate in the brain that forms tangle-like structures - but this is only descriptive, we have not yet understood the mechanisms linking this pathology to the disease phenotype."

Junmin Peng, Ph.D., St. Jude Departments of Structural Biology and Developmental Neurobiology

Unique model links RNA splicing defects to neuronal hyperexcitability

The researchers created a novel mouse model of RNA splicing defects called N40K-Tg. The scientists observed profound neurodegeneration when they deregulated the splicing machinery, but they wanted to understand why this was the case.

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“Splicing machines are so important, and creating a model to study it in the lab was a real challenge,” Peng said. "We were able to create a model of splicing disorder that only occurs in neurons. This model demonstrates a splicing disorder that causes both neuronal toxicity and cognitive impairment."

Inhibitory neuron activity prevents the brain from becoming overexcited. When a scientist suppresses inhibitory neuron activity, the neurons become more active, but it can cause toxicity. The researchers found a significant impact on synaptic proteins, particularly the proteins involved in inhibitory neuron activity.

"Excitatory toxicity is very important because it is already known in the field of Alzheimer's disease," Peng said. "As early as 20 to 30 years ago, people recognized that neurons become superexcited, and now we are finding that the splicing machinery may contribute to the excitatory toxicity seen in Alzheimer's patients."

RNA splicing defects and β-amyloid aggregation combined

A hallmark of Alzheimer's disease is the presence of aggregates of β-amyloid and tau in the brain. Peng's previous work showed that U1 snRNP also forms aggregates in the brain, but scientists were unable to study the role of U1 snRNP function in disease until they developed a model that disrupted U1 snRNP function and caused RNA splicing defects.

To understand how the RNA splicing defects associated with β-amyloid aggregation behave, the researchers crossed their mouse model with one for β-amyloid. Together, the two types of toxic insults alter the brain's transcriptome and proteome, deregulate synaptic proteins, and accelerate cognitive decline.

“From initial behavior to cell biology to molecular mechanism, we characterized the potential contribution of the RNA splicing machinery to neuronal excitatory toxicity in Alzheimer's disease,” Peng said.

This crossbred mouse model more closely resembles Alzheimer's disease in humans than previous models and could be useful for future research into the disease.

Source:

St. Jude Children's Research Hospital

Reference:

Chen, PC.et al. (2022) Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment. Aging in nature. doi.org/10.1038/s43587-022-00290-0.

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