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Written byWang CongEditorWang Duoyu typesettingShui Chengwen
Alzheimer's disease, AD , commonly known as "Alzheimer's disease", is a serious neurodegenerative disease, patients usually appear memory loss, learning ability weakened symptoms, accompanied by emotional regulation disorders and loss of exercise ability, greatly affecting the development of
individuals, families and even society.
Currently, about 50 million people worldwide suffer from Alzheimer's disease
.
As human life expectancy increases and the aging society intensifies, the prevalence of Alzheimer's disease is also increasing, and it is expected that by 2050, the number of Alzheimer's disease patients will increase to more than
150 million.
Unfortunately, due to the complex etiology, the scientific community has not yet deciphered the specific mechanism of Alzheimer's disease, which has also led to fierce competition and controversy in the entire Alzheimer's disease drug research and development field
.
Recently, the team of Professor Peng Junmin of St.
Jude Children's Research Hospital published a paper in Nature Aging: Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment.
The research team created mouse models of RNA splicing errors and β-amyloid aggregation, which are closer to human Alzheimer's disease than previous animal models, using which U1 small ribonucleoprotein (U1 snRNP) was found Mediated dysfunction of RNA splicing can play a role
in the pathogenesis of Alzheimer's disease by causing neuronal hyperexcitation and cognitive impairment.
According to the central law, DNA is transcribed to mRNA, mRNA is translated into proteins, and RNA splicing is an important step
between transcription and translation.
In eukaryotes, the precursor mRNA transcribed from DNA undergoes RNA splicing, removes introns, and stitches together exon parts to form mature mRNAs
.
Professor Peng Junmin said that RNA splicing is particularly important in the brain because the brain has more cellular diversity than any other organ in the body, and RNA splicing is an important process
that leads to protein diversity in brain cells.
Junmin Peng received his bachelor's degree from Wuhan University, his Ph.
D.
in biochemistry from the University of Iowa, and his postdoctoral fellowship
at Harvard University.
After 9 years at Emory University, he joined St.
Jude Children's Research Hospital in 2011 as a researcher in the Department of Structural Biology and Developmental Neurobiology and director of the Center for
Proteomics and Metabolomics.
His main research interests are to understand the mechanisms
of human diseases such as cancer, Alzheimer's disease and the human immune response through proteomics, metabolomics and systems biology.
Previous research by Peng Junmin and other research team has shown that U1 small ribonucleoprotein (U1 snRNP), an essential component in RNA splicing, accumulates
in the brains of Alzheimer's patients.
The latest study by Peng Junmin's team shows that the dysfunction of U1 snRNP can lead to RNA splicing disorders, which contributes to neurodegeneration, which opens up a new research avenue
for the treatment of Alzheimer's disease.
Peng said that the team's previous work showed that U1 snRNP is an aggregate in the brain that forms tangled structures, but it is only a descriptive study, and this study reveals the connection and mechanism
between this pathological phenomenon and the disease phenotype.
RNA splicing is important, but creating a model to study in the lab is a real challenge
.
In this study, Peng's team created a mouse model of RNA splicing defects called N40K-Tg, which only has RNA splicing errors in brain neurons, through which the team found that such splicing errors in neurons can lead to neuronal toxicity and cognitive impairment, and neurodegeneration in mice
.
N40K-Tg mice showed that neuronal loss and cognitive impairment
inhibited neuronal activity to prevent brain overexcitability
.
However, if the activity of the inhibitory neurons itself is inhibited, the neurons become more active, causing toxicity
.
As early as two or three decades ago, researchers recognized the problem of
abnormal neuronal excitement in Alzheimer's patients.
The latest study found that neuronal synaptic proteins in mouse models with RNA splicing-deficiencies were significantly affected, especially those
involved in inhibiting neuronal activity.
This suggests that RNA splicing mechanisms may be responsible for
neuronal excitotoxicity in Alzheimer's patients.
An important hallmark of Alzheimer's disease is the aggregation
of β-amyloid and tau proteins in the brain.
Previous research by Peng Junmin's team revealed that U1 snRNP also forms this protein aggregate in the brain, but the specific role
of U1 snRNP in Alzheimer's disease is unclear.
In this study, in order to understand the behavior of RNA splicing defects in the case of β-amyloid aggregation, they constructed a mouse model with RNA splicing defects and β-amyloid aggregation, two toxic effects that together reshape the transcriptome and proteome of mouse brains, deregulate neuronal synaptic proteins, and accelerate cognitive decline
.
Peng Junmin said that from the initial behavioral and cell biology discoveries to the current molecular mechanism, this series of studies has revealed the potential contribution of RNA splicing mechanism to the excitotoxicity of neurons in Alzheimer's disease, and also opened up new research avenues
for the treatment of Alzheimer's disease.
This crossover mouse model of RNA splicing errors and β-amyloid aggregation, which is closer to human Alzheimer's disease than previous animal models, will contribute to future Alzheimer's disease research
.
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