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RNA Splicing Defects Contribute to Neurodegeneration in Alzheimer Disease, Model Suggests
Image Credit: St. Jude Children's Research Hospital
RNA splicing machinery dysfunction may cause neuronal excitatory toxicity and, thus, cognitive impairment in Alzheimer disease, a new model created by researchers at St. Jude Children's Research Hospital demonstrated. The findings were published in the journal Nature Aging.
Using a mouse model that closely resembles the disease in humans, researchers sought to understand how RNA splicing—the process that removes non-coding genetic sequences and joins protein-coding sequences together—contributes to neurodegeneration in Alzheimer disease.
"Here we present a causative role of U1 small nuclear ribonucleoprotein (snRNP) dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70k," Ping-Chung Chen, PhD, et al wrote in the study. The N40K-Tg model demonstrates that when inhibitory neuron activity is repressed, the neurons become more active resulting in toxicity. This excitatory toxicity is what is observed in Alzheimer patients, researchers found.
Related: Three Molecular Subtypes of Alzheimer Disease Identified
β-amyloid and tau aggregates in the brain are hallmarks of Alzheimer disease. Researchers wanted to better understand how the observed RNA splicing defects behave in the context of β-amyloid aggregation, so they developed a crossed mouse model—one that more closely resembles the disease in humans.
This crossed mouse model “indicates that the RNA splicing defect synergizes with the amyloid cascade to remodel the brain transcriptome and proteome, deregulate synaptic proteins, and accelerate cognitive decline,” researchers wrote in the study.
"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," corresponding author Junmin Peng, PhD, director of the Center for Proteomics and Metabolomics at St. Jude, said in a press release. "We didn't understand the mechanisms that link his pathology to the disease phenotype until now."
“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 disease,” Peng said.
The Alzheimer's Association estimates over 6.5 million people in the US over 65, about 1 in 9, are living with the disease. By 2050 it is estimated that 13 million US citizens will be diagnosed with Alzheimer, a 116% increase.
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