Nature sub-journal: Mechanisms by which RNA splicing defects lead to Alzheimer's disease

Researchers have puzzled the neurodegenerative disease Alzheimer's disease for decades, but treatments to stop or reverse the disease's effects on the brain remain
elusive.
Scientists at St.
Jude Children's Research Hospital recently added an important piece to the puzzle by creating a mouse model
of human disease that is closer to previous models.
The findings are published today in the
journal 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 gene sequences and links protein coding sequences together.

"RNA splicing is an important step between transcription and translation," said
corresponding author Junmin Peng, Ph.
D.
"This is especially important in the brain because we know that the brain has more cellular diversity than any other organ in the body, and splicing is considered an important process
for generating protein diversity.
"

Previous work by Peng and others revealed a particular component of the RNA splicing mechanism, called U1 small ribonucleoprotein (snRNP), which produces aggregates
in the brains of Alzheimer's patients.
The U1 snRNP complex is essential
in RNA splicing.

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

"Our previous work has shown that U1 snRNP is an aggregate in the brain that forms tangled structures, but this is only descriptive, and until now we understood the mechanism
of connection between this pathology and disease phenotype," Peng said.

The unique model links RNA splicing defects to neuronal hyperexcitability

The researchers created an RNA splicing-deficient mouse model
called N40K-Tg.
When the scientists uncontrolled the splicing mechanism, they observed basic neurodegeneration, but they wanted to understand why
.

"Splicing machinery is so important that creating a model in the lab to study it is a real challenge
," Peng said.
We were able to create a model
of stitching dysfunction that occurs only in neurons.
This model demonstrates that splicing dysfunction can lead to neuronal toxicity and cognitive impairment
.
”

Inhibiting neuronal activity prevents brain overexcitability
.
If the activity of the inhibitory neuron is inhibited, the neuron becomes more active, but it causes toxicity
.
The researchers found that synaptic proteins in the new mouse model were significantly affected, particularly those
involved in inhibiting neuronal activity.

"Excitotoxicity is very important because it's already known in the Alzheimer's field," Peng said
.
"Even 20-30 years ago, it was recognized that neurons became super excited, and now we find that splicing mechanisms may be responsible for
excitotoxicity in Alzheimer's patients.
"

RNA splicing defects and β-amyloid aggregation binding

One hallmark of Alzheimer's disease is the aggregation
of β-amyloid and tau proteins in the brain.
Peng's previous work revealed 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 interferes with U1 snRNP function leading to RNA splicing defects.

To understand how RNA splicing defects behave in the case of β-amyloid aggregation, the researchers crossed
their mouse model with the β-amyloid model.
Together, these two types of toxic attacks reshape the brain's transcriptome and proteome, unregulating synaptic proteins and accelerating cognitive decline
.

"From the initial behavior, to cell biology, and now to molecular mechanisms, we have described the potential contribution
of RNA splicing mechanisms to the excitatory toxicity of neurons in Alzheimer's disease," Peng said.
This crossover mouse model is closer to Alzheimer's in humans than earlier models and may be useful
for future disease research.

Ping-Chung Chen, Xian Han, Timothy I.
Shaw, Yingxue Fu, Huan Sun, Mingming Niu, Zhen Wang, Yun Jiao, Brett J.
W.
Teubner, Donnie Eddins, Lauren N.
Beloate, Bing Bai, Joseph Mertz, Yuxin Li, Ji-Hoon Cho, Xusheng Wang, Zhiping Wu, Danting Liu, Suresh Poudel, Zuo-Fei Yuan, Ariana Mancieri, Jonathan Low, Hyeong-Min Lee, Mary H.
Patton, Laurie R.
Earls, Elizabeth Stewart, Peter Vogel, Yawei Hui , Shibiao Wan, David A.
Bennett, Geidy E.
Serrano, Thomas G.
Beach, Michael A.
Dyer, Richard J.
Smeyne, Tudor Moldoveanu, Taosheng Chen, Gang Wu, Stanislav S.
Zakharenko, Gang Yu, Junmin Peng.
Alzheimer’ s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment.
Nature Aging, 2022; DOI: 10.
1038/s43587-022-00290-0