neurodegenerative diseases | Tsinghua University School of Medicine/Tsinghua-Peking University Life Joint Center Jia Yichang team found that intron splicing disorder leads to neurodegeneration

May 2023Protein & Cellpublished a cover article entitled "A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration". The research team of Professor Jia Yichang from Tsinghua-Peking University Life Joint Center and Tsinghua University Medical College found outmRNA provides a new mechanism for the occurrence of neurodegenerative diseases.

pre-mRNA splicing (pre-mRNA splicing) is a very important regulatory step in the process of gene expression. It is responsible for the intron (intron) in the pre-mRNA (pre-mRNA) and the exon (protein-encoding part) is connected to form the mature mRNA, so that the functional protein can be produced during the translation process. More than 90% of human genes have undergone alternative splicing (alternative splicing). Alternative splicing refers to combining exons of the same gene in precursor mRNA molecules through different splicing methods to produce a variety of different mRNAs, thus encoding a variety of proteins. Thus, pre-mRNA splicing (pre-mRNA splicing) plays an important role in gene function regulation and protein diversity. In recent years, more and more evidences suggest that the disorder of RNA metabolism caused by abnormal splicing of pre-mRNA may be an important cause of neurodegenerative diseases.

Intron retention (intron retention) is one of the modes of alternative splicing, which refers to the transcription process, part of the intron is not spliced out, but retained in the mature transcript. However, because introns usually introduce early termination codons into transcripts, and transcripts carrying early termination codons are degraded by nonsense-mediated mRNA degradation (nonsense-mediated decay, NMD) mechanisms, it is generally believed that there will be no protein products. In 2015, US Nobel laureate Phillip Sharp's team discovered a class of intron-retained transcripts (intron-detaining transcripts), which are located in the nucleus and have almost completed the post-processing of all mature mRNA as a post-transcriptional regulatory mechanism to finely regulate gene expression (Genes Dev .,2015). Considering that the average size of human genes is about 30kb and the transcription rate of mRNA is about 2-4kb/min, Peter Scheiffele of the University of Basel and others proposed that intron-retained transcripts can enable cells to quickly respond to changes in the surrounding environment, because intron-retained transcripts do not need to go through a time-consuming mRNA transcription process when responding quickly to environmental changes (Neuron., 2016). however,we still do not understand the molecular mechanism and the biological consequences of misregulation in this process.

In previous studies, U2 snRNA(U2 small nuclear RNA) is known to be an important component involved in pre-mRNA splicing. In 2012, Dr. Jia Yichang and others found a 5-nucleotide deletion of U2 snRNA in mouse brain. This mutation can lead to a large number of intron-retained transcripts and neurodegenerative diseases (Cell, 2012). Based on this finding, in this study, we identified that half-dose insufficiency of SNIP1(Smad Nuclear Interacting Protein 1) can greatly alleviate U2 mutation-induced intron-retained transcript accumulation and neurodegeneration through mutagen-mediated forward genetic screening in mice. Our research results include:

1) More than 90% of intron retention transcripts contain only 1-2 introns, which is more conducive to the rapid response of cells to produce mature mRNA.

2) The previously reported U2 mutations did not increase the retention of new intron transcripts, but allowed these transcripts to accumulate in the nucleus.

3) The sequences of these retained introns are evolutionarily highly conserved and intron retained transcripts are finely regulated during cerebellar development.

4) There are multiple intermediate states in the process of splicing (spliceosome), where Bact(activated spliceosome) is an important intermediate state, Bactsplice has been activated but does not have catalytic activity, only after a series of conformational and compositional transformations to become B *(catalytically activated spliceosome), with the ability to complete the first step of splicing to ester branching reaction (transesterification). We foundSNIP1exists in Bact, using SNIP1and Bactprotein rather than B * protein can enrich the transcript of intron retention.Based on this result, wefirst proposed the concept of spliceosome suspension (Spliceosomepausing), and proposedspliceosomes were suspended on transcripts of intron retention in Bactintermediate state.

5) The interaction of SNIP1 and RNPS1(RNA Binding Protein With Serine Rich Domain 1) regulates intron retention, where RNPS1 suspends the spliceosome in Bactintermediate state;

6) Finally, conditional knockout in cerebellar granule neuronsSnip1leads to the accumulation of intron-retained transcripts, suggesting that SNIP1 as a spliceosome protein facilitates splicing of intron-retained transcripts by spliceosomes.

Figure 1. The working principle of splice suspension (Spliceosome pausing) and its contribution to neurodegenerative diseases. The splicing of constitutively spliced introns (Constitutive introns) and trapped introns (Detained introns) have different kinetic properties, the former occurring simultaneously with transcription (Co-transcriptional) and the latter after transcription (Post-transcriptional).mutant (e. g., U2 mutation or Snip1 conditional knockout) or dysfunctional (e. g., senescence) splicers have less influence on the splicing of constitutive introns and are more likely to affect retained introns, which may be an important contributor to disease pathogenesis.

In this study, we observed a large accumulation of intron-retained transcripts in the brains of aged mice. Whereas a large number of intron-retained transcripts were also found in the brains of neurodegenerative patients (Aging Cell .,2019), the reported working principle of splice suspension (Spliceosome pausing) may have an important contribution to the pathogenesis of neurodegenerative diseases (Figure 1).

, is the first author of the paper, and Professor Jia Yichang is the corresponding author of the paper. Zheng Qian, a doctoral student of Tsinghua University School of Medicine, Zhang Xue, a postdoctoral fellow of Tsinghua University School of Medicine, Dr. Park Xuejiao of Tsinghua University School of Life Sciences, and Dr. Luo Li of Tsinghua University Brain and Intelligence Laboratory have all made important contributions. This work was supported by the Joint Center for Life Sciences, the IDG/McGovern Institute, the National Natural Science Foundation of China and the Beijing Municipal Commission of Science and Technology.

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[1] Boutz, P.L., Bhutkar, A., and Sharp, P.A. (2015). Detained introns are a novel, widespread class of post-transcriptionally spliced introns.Genes Dev29,63-80.

[2] Mauger, O., Lemoine, F., and Scheiffele, P. (2016). Targeted Intron Retention and Excision for Rapid Gene Regulation in Response to Neuronal Activity.Neuron92,1266-1278.

[3] Adusumalli, S., Ngian, Z.K., Lin, W.Q., Benoukraf, T., and Ong, C.T. (2019). Increased intron retention is a post‐transcriptional signature associated with progressive aging andAlzheimer's disease.Aging Cell18, e12928.