Alternative splicing in neurodegenerative disease and the promise of RNA therapies

Chow, L. T., Gelinas, R. E., Broker, T. R. & Roberts, R. J. An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA. Cell 12, 1–8 (1977).

Article  CAS  PubMed  Google Scholar 

Amara, S. G., Jonas, V., Rosenfeld, M. G., Ong, E. S. & Evans, R. M. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298, 240–244 (1982).

Article  CAS  PubMed  Google Scholar 

Wang, E. T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470–476 (2008).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Pan, Q., Shai, O., Lee, L. J., Frey, B. J. & Blencowe, B. J. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet. 40, 1413–1415 (2008).

Article  CAS  PubMed  Google Scholar 

Yeo, G., Holste, D., Kreiman, G. & Burge, C. B. Variation in alternative splicing across human tissues. Genome Biol. 5, R74 (2004).

Article  PubMed Central  PubMed  Google Scholar 

Barbosa-Morais, N. L. et al. The evolutionary landscape of alternative splicing in vertebrate species. Science 338, 1587–1593 (2012).

Article  CAS  PubMed  Google Scholar 

Vuong, C. K., Black, D. L. & Zheng, S. The neurogenetics of alternative splicing. Nat. Rev. Neurosci. 17, 265–281 (2016).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Furlanis, E. & Scheiffele, P. Regulation of neuronal differentiation, function, and plasticity by alternative splicing. Annu. Rev. Cell Dev. Biol. 34, 451–469 (2018).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Ule, J. & Blencowe, B. J. Alternative splicing regulatory networks: functions, mechanisms, and evolution. Mol. Cell 76, 329–345 (2019).

Article  CAS  PubMed  Google Scholar 

Zheng, S. Alternative splicing programming of axon formation. Wiley Interdiscip. Rev. RNA 11, e1585 (2020).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Traunmüller, L., Gomez, A. M., Nguyen, T.-M. & Scheiffele, P. Control of neuronal synapse specification by a highly dedicated alternative splicing program. Science 352, 982–986 (2016).

Article  PubMed  Google Scholar 

Mauger, O. & Scheiffele, P. Beyond proteome diversity: alternative splicing as a regulator of neuronal transcript dynamics. Curr. Opin. Neurobiol. 45, 162–168 (2017).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Zhang, M. et al. Axonogenesis is coordinated by neuron-specific alternative splicing programming and splicing regulator PTBP2. Neuron 101, 690–706.e10 (2019).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Lin, L., Zhang, M., Stoilov, P., Chen, L. & Zheng, S. Developmental attenuation of neuronal apoptosis by neural-specific splicing of Bak1 microexon. Neuron 107, 1180–1196.e8 (2020). This study demonstrates that the neuronal splicing of a microexon in Bak1 reduces apoptosis competence and is necessary for supporting neuronal and animal survival, providing genetic evidence highlighting the essential role of neuronal splicing in brain development and organism survival.

Article  CAS  PubMed Central  PubMed  Google Scholar 

Gonatopoulos-Pournatzis, T. & Blencowe, B. J. Microexons: at the nexus of nervous system development, behaviour and autism spectrum disorder. Curr. Opin. Genet. Dev. 65, 22–33 (2020).

Article  CAS  PubMed  Google Scholar 

Ha, K. C. H., Sterne-Weiler, T., Morris, Q., Weatheritt, R. J. & Blencowe, B. J. Differential contribution of transcriptomic regulatory layers in the definition of neuronal identity. Nat. Commun. 12, 335 (2021).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Vuong, J. K., Ergin, V., Chen, L. & Zheng, S. Multilayered regulations of alternative splicing, NMD, and protein stability control temporal induction and tissue-specific expression of TRIM46 during axon formation. Nat. Commun. 13, 2081 (2022).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Zheng, S. et al. PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2. Nat. Neurosci. 15, 381–388 (2012).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Zhang, X. et al. Cell type-specific alternative splicing governs cell fate in the developing cerebral cortex. Cell 166, 1147–1162.e15 (2016).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Havens, M. A. & Hastings, M. L. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 44, 6549–6563 (2016).

Article  PubMed Central  PubMed  Google Scholar 

Bennett, C. F., Krainer, A. R. & Cleveland, D. W. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu. Rev. Neurosci. 42, 385–406 (2019).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Nagasaki, H., Arita, M., Nishizawa, T., Suwa, M. & Gotoh, O. Species-specific variation of alternative splicing and transcriptional initiation in six eukaryotes. Gene 364, 53–62 (2005).

Article  CAS  PubMed  Google Scholar 

Chen, M. & Manley, J. L. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat. Rev. Mol. Cell Biol. 10, 741–754 (2009).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Garcia-Blanco, M. A., Baraniak, A. P. & Lasda, E. L. Alternative splicing in disease and therapy. Nat. Biotechnol. 22, 535–546 (2004).

Article  CAS  PubMed  Google Scholar 

Ule, J. et al. An RNA map predicting Nova-dependent splicing regulation. Nature 444, 580–586 (2006).

Article  CAS  PubMed  Google Scholar 

Wegener, M. & Müller-McNicoll, M. in The Biology of mRNA: Structure and Function (eds Oeffinger, M. & Zenklusen, D.) 83–112 (Springer International, 2019).

Cáceres, J. F. & Kornblihtt, A. R. Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet. 18, 186–193 (2002).

Article  PubMed  Google Scholar 

Fu, X.-D. & Ares, M. Context-dependent control of alternative splicing by RNA-binding proteins. Nat. Rev. Genet. 15, 689–701 (2014).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Su, C.-H., Dhananjaya, D. & Tarn, W.-Y. Alternative splicing in neurogenesis and brain development. Front. Mol. Biosci. 5, 12 (2018).

Article  PubMed Central  PubMed  Google Scholar 

Ohkura, N., Takahashi, M., Yaguchi, H., Nagamura, Y. & Tsukada, T. Coactivator-associated arginine methyltransferase 1, CARM1, affects pre-mRNA splicing in an isoform-specific manner. J. Biol. Chem. 280, 28927–28935 (2005).

Article  CAS  PubMed  Google Scholar 

Cheng, D., Côté, J., Shaaban, S. & Bedford, M. T. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol. Cell 25, 71–83 (2007).

Article  PubMed  Google Scholar 

Chen, Y.-C. et al. Protein arginine methylation facilitates cotranscriptional recruitment of pre-mRNA splicing factors. Mol. Cell Biol. 30, 5245–5256 (2010).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Gunderson, F. Q. & Johnson, T. L. Acetylation by the transcriptional coactivator Gcn5 plays a novel role in co-transcriptional spliceosome assembly. PLoS Genet. 5, e1000682 (2009).

Article  PubMed Central  PubMed  Google Scholar 

Martinez, E. et al. Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo. Mol. Cell Biol. 21, 6782–6795 (2001).

Article  CAS  PubMed Central  PubMed  Google Scholar 

Naftelberg, S., Schor, I. E., Ast, G. & Kornblihtt, A. R. Regulation of alternative splicing through coupling with transcription and chromatin structure. Annu. Rev. Biochem. 84, 165–198 (2015).

Article  CAS  PubMed  Google Scholar 

Keren, H., Lev-Maor, G. & Ast, G. Alternative splicing and evolution: diversification, exon definition and function. Nat. Rev. Genet. 11, 345–355 (2010).

Article  CAS  PubMed  Google Scholar 

留言 (0)

沒有登入
gif