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Alternative Splicing in Human Biology and Disease

Part of the Methods in Molecular Biology book series (MIMB,volume 2537)

Abstract

Alternative pre-mRNA splicing allows for the production of multiple mRNAs from an individual gene, which not only expands the protein-coding potential of the genome but also enables complex mechanisms for the post-transcriptional control of gene expression. Regulation of alternative splicing entails a combinatorial interplay between an abundance of trans-acting splicing factors, cis-acting regulatory sequence elements and their concerted effects on the core splicing machinery. Given the extent and biological significance of alternative splicing in humans, it is not surprising that aberrant splicing patterns can cause or contribute to a wide range of diseases. In this introductory chapter, we outline the mechanisms that govern alternative pre-mRNA splicing and its regulation and discuss how dysregulated splicing contributes to human diseases affecting the motor system and the brain.

Key words

  • Alternative splicing
  • snRNPs
  • Trans-acting splicing factors
  • Cis-acting regulatory elements
  • Myotonic dystrophy type 1
  • Spinal muscular atrophy
  • Amyotrophic lateral sclerosis
  • Frontotemporal dementia with parkinsonism linked to chromosome 17

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References

  1. Sharp PA (1994) Split genes and RNA splicing. Cell 77:805–815. https://doi.org/10.1016/0092-8674(94)90130-9

    CAS  CrossRef  PubMed  Google Scholar 

  2. Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336

    CAS  PubMed  CrossRef  Google Scholar 

  3. Lee Y, Rio DC (2015) Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem 84:291–323

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  4. Barbosa-Morais NL, Irimia M, Pan Q et al (2012) The evolutionary landscape of alternative splicing in vertebrate species. Science 338:1587–1593. https://doi.org/10.1126/science.1230612

    CAS  CrossRef  PubMed  Google Scholar 

  5. Merkin J, Russell C, Chen P, Burge CB (2012) Evolutionary dynamics of gene and isoform regulation in mammalian tissues. Science 338:1593–1599. https://doi.org/10.1126/science.1228186

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  6. Shin C, Manley JL (2004) Cell signalling and the control of pre-mRNA splicing. Nat Rev Mol Cell Biol 5:727–738

    CAS  PubMed  CrossRef  Google Scholar 

  7. Xing Y, Lee C (2006) Alternative splicing and RNA selection pressure—evolutionary consequences for eukaryotic genomes. Nat Rev Genet 7:499–509

    CAS  PubMed  CrossRef  Google Scholar 

  8. Nilsen TW, Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463:457–463

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  9. Blencowe BJ (2006) Alternative splicing: new insights from global analyses. Cell 126:37–47

    CAS  PubMed  CrossRef  Google Scholar 

  10. Will CL, Lührmann R (2011) Spliceosome structure and function. Cold Spring Harb Perspect Biol 3:1–2. https://doi.org/10.1101/cshperspect.a003707

    CAS  CrossRef  Google Scholar 

  11. Jurica MS, Moore MJ (2003) Pre-mRNA splicing: awash in a sea of proteins. Mol Cell 12:5–14

    CAS  PubMed  CrossRef  Google Scholar 

  12. Stark H, Dube P, Luührmann R, Kastner B (2001) Arrangement of RNA and proteins in the spliceosomal U1 small nuclear ribonucleoprotein particle. Nature 409:539–542. https://doi.org/10.1038/35054102

    CAS  CrossRef  PubMed  Google Scholar 

  13. Urlaub H, Raker VA, Kostka S, Lührmann R (2001) Sm protein-Sm site RNA interactions within the inner ring of the spliceosomal snRNP core structure. EMBO J 20:187–196. https://doi.org/10.1093/emboj/20.1.187

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  14. Wahl MC, Will CL, Lührmann R (2009) The spliceosome: design principles of a dynamic RNP machine. Cell 136:701–718

    CAS  PubMed  CrossRef  Google Scholar 

  15. Kastner B, Will CL, Stark H, Lührmann R (2019) Structural insights into nuclear pre-mRNA splicing in higher eukaryotes. Cold Spring Harb Perspect Biol 11:a032417. https://doi.org/10.1101/cshperspect.a032417

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  16. Wilkinson ME, Charenton C, Nagai K (2020) RNA splicing by the spliceosome. Annu Rev Biochem 89:359–388

    CAS  PubMed  CrossRef  Google Scholar 

  17. Yan C, Wan R, Shi Y (2019) Molecular mechanisms of pre-mRNA splicing through structural biology of the spliceosome. Cold Spring Harb Perspect Biol 11:a032409. https://doi.org/10.1101/cshperspect.a032409

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  18. Cordin O, Beggs JD (2013) RNA helicases in splicing. RNA Biol 10:83–95

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  19. Hoskins AA, Friedman LJ, Gallagher SS et al (2011) Ordered and dynamic assembly of single spliceosomes. Science 331:1289–1295. https://doi.org/10.1126/science.1198830

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  20. Kondo Y, Oubridge C, van Roon AMM, Nagai K (2015) Crystal structure of human U1 snRNP, a small nuclear ribonucleoprotein particle, reveals the mechanism of 5′ splice site recognition. Elife 4:e04986. https://doi.org/10.7554/eLife.04986

    CrossRef  PubMed Central  Google Scholar 

  21. Berglund JA, Abovich N, Rosbash M (1998) A cooperative interaction between U2AF65 and mBBP/SF1 facilitates branchpoint region recognition. Genes Dev 12:858–867. https://doi.org/10.1101/gad.12.6.858

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  22. Plaschka C, Lin PC, Charenton C, Nagai K (2018) Prespliceosome structure provides insights into spliceosome assembly and regulation. Nature 559:419–422. https://doi.org/10.1038/s41586-018-0323-8

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  23. Charenton C, Wilkinson ME, Nagai K (2019) Mechanism of 5′ splice site transfer for human spliceosome activation. Science 364:362–367. https://doi.org/10.1126/science.aax3289

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  24. Haselbach D, Komarov I, Agafonov DE et al (2018) Structure and conformational dynamics of the human Spliceosomal Bact complex. Cell 172:454–464.e11. https://doi.org/10.1016/j.cell.2018.01.010

    CAS  CrossRef  PubMed  Google Scholar 

  25. Zhang X, Yan C, Hang J et al (2017) An atomic structure of the human spliceosome. Cell 169:918–929.e14. https://doi.org/10.1016/j.cell.2017.04.033

    CAS  CrossRef  PubMed  Google Scholar 

  26. Zhang X, Zhan X, Yan C et al (2019) Structures of the human spliceosomes before and after release of the ligated exon. Cell Res 29:274–285. https://doi.org/10.1038/s41422-019-0143-x

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  27. Patel AA, Steitz JA (2003) Splicing double: insights from the second spliceosome. Nat Rev Mol Cell Biol 4:960–970

    CAS  PubMed  CrossRef  Google Scholar 

  28. Will CL, Lührmann R (2005) Splicing of a rare class of introns by the U12-dependent spliceosome. Biol Chem 386:713–724

    CAS  PubMed  CrossRef  Google Scholar 

  29. Turunen JJ, Niemelä EH, Verma B, Frilander MJ (2013) The significant other: splicing by the minor spliceosome. Wiley Interdiscip Rev RNA 4:61–76

    CAS  PubMed  CrossRef  Google Scholar 

  30. Jutzi D, Akinyi MV, Mechtersheimer J et al (2018) The emerging role of minor intron splicing in neurological disorders. Cell Stress 2:40–54

    PubMed  PubMed Central  CrossRef  Google Scholar 

  31. Verma B, Akinyi MV, Norppa AJ, Frilander MJ (2018) Minor spliceosome and disease. Semin Cell Dev Biol 79:103–112

    CAS  PubMed  CrossRef  Google Scholar 

  32. Niemelä EH, Frilander MJ (2014) Regulation of gene expression through inefficient splicing of U12-type introns. RNA Biol 11:1325–1329

    PubMed  CrossRef  Google Scholar 

  33. Younis I, Dittmar K, Wang W et al (2013) Minor introns are embedded molecular switches regulated by highly unstable U6atac snRNA. Elife 2:e00780. https://doi.org/10.7554/eLife.00780

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  34. Patel AA, McCarthy M, Steitz JA (2002) The splicing of U12-type introns can be a rate-limiting step in gene expression. EMBO J 21:3804–3815. https://doi.org/10.1093/emboj/cdf297

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  35. Wang Z, Rolish ME, Yeo G et al (2004) Systematic identification and analysis of exonic splicing silencers. Cell 119:831–845. https://doi.org/10.1016/j.cell.2004.11.010

    CAS  CrossRef  PubMed  Google Scholar 

  36. Matlin AJ, Clark F, Smith CWJ (2005) Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 6:386–398

    CAS  PubMed  CrossRef  Google Scholar 

  37. Wang Z, Burge CB (2008) Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 14:802–813

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  38. Smith CWJ, Valcárcel J (2000) Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem Sci 25:381–388

    CAS  PubMed  CrossRef  Google Scholar 

  39. Shepard PJ, Hertel KJ (2008) Conserved RNA secondary structures promote alternative splicing. RNA 14:1463–1469. https://doi.org/10.1261/rna.1069408

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

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

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  42. Shepard PJ, Hertel KJ (2009) The SR protein family. Genome Biol 10:242

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  43. Long JC, Caceres JF (2009) The SR protein family of splicing factors: master regulators of gene expression. Biochem J 417:15–27

    CAS  PubMed  CrossRef  Google Scholar 

  44. Berget SM (1995) Exon recognition in vertebrate splicing. J Biol Chem 270:2411–2414

    CAS  PubMed  CrossRef  Google Scholar 

  45. Li X, Liu S, Zhang L et al (2019) A unified mechanism for intron and exon definition and back-splicing. Nature 573:375–380. https://doi.org/10.1038/s41586-019-1523-6

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  46. Shen H, Kan JLC, Green MR (2004) Arginine-serine-rich domains bound at splicing enhancers contact the branchpoint to promote Prespliceosome assembly. Mol Cell 13:367–376. https://doi.org/10.1016/S1097-2765(04)00025-5

    CAS  CrossRef  PubMed  Google Scholar 

  47. Kanopka A, Muhlemann O, Akusjarvi G (1996) Inhibition by SR proteins splicing of a regulated adenovirus pre-mRNA. Nature 381:535–538. https://doi.org/10.1038/381535a0

    CAS  CrossRef  PubMed  Google Scholar 

  48. Dreyfuss G, Matunis MJ, Piñol-Roma S, Burd CG (1993) hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem 62:289–321

    CAS  PubMed  CrossRef  Google Scholar 

  49. Geuens T, Bouhy D, Timmerman V (2016) The hnRNP family: insights into their role in health and disease. Hum Genet 135:851–867

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  50. Witten JT, Ule J (2011) Understanding splicing regulation through RNA splicing maps. Trends Genet 27:89–97

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  51. Darnell RB (2010) HITS-CLIP: panoramic views of protein-RNA regulation in living cells. Wiley Interdiscip Rev RNA 1:266–286. https://doi.org/10.1002/wrna.31

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  52. Zhu J, Mayeda A, Krainer AR (2001) Exon identity established through differential antagonism between exonic splicing silencer-bound hnRNP A1 and enhancer-bound SR proteins. Mol Cell 8:1351–1361. https://doi.org/10.1016/S1097-2765(01)00409-9

    CAS  CrossRef  PubMed  Google Scholar 

  53. Mayeda A, Krainer AR (1992) Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2. Cell 68:365–375. https://doi.org/10.1016/0092-8674(92)90477-T

    CAS  CrossRef  PubMed  Google Scholar 

  54. König J, Zarnack K, Rot G et al (2010) ICLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 17:909–915. https://doi.org/10.1038/nsmb.1838

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  55. Oberstrass FC, Auwetor SD, Erat M et al (2005) Structural biology - structure of PTB bound to RNA: specific binding and implications for splicing regulation. Science 309:2054–2057. https://doi.org/10.1126/science.1114066

    CAS  CrossRef  PubMed  Google Scholar 

  56. Blanchette M, Chabot B (1999) Modulation of exon skipping by high-affinity hnRNP A1-binding sites and by intron elements that repress splice site utilization. EMBO J 18:1939–1952. https://doi.org/10.1093/emboj/18.7.1939

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  57. Förch P, Puig O, Martínez C et al (2002) The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment to 5′ splice sites. EMBO J 21:6882–6892. https://doi.org/10.1093/emboj/cdf668

    CrossRef  PubMed  PubMed Central  Google Scholar 

  58. Izquierdo JM, Majós N, Bonnal S et al (2005) Regulation of fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition. Mol Cell 19:475–484. https://doi.org/10.1016/j.molcel.2005.06.015

    CAS  CrossRef  PubMed  Google Scholar 

  59. Sharma S, Maris C, Allain FHT, Black DL (2011) U1 snRNA directly interacts with polypyrimidine tract-binding protein during splicing repression. Mol Cell 41:579–588. https://doi.org/10.1016/j.molcel.2011.02.012

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  60. Martelly W, Fellows B, Senior K et al (2019) Identification of a noncanonical RNA binding domain in the U2 snRNP protein SF3A1. RNA 25:1509–1521. https://doi.org/10.1261/rna.072256.119

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  61. Jutzi D, Campagne S, Schmidt R et al (2020) Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis. Nat Commun 11:6341. https://doi.org/10.1038/s41467-020-20191-3

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  62. Bonnal S, Martínez C, Förch P et al (2008) RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition. Mol Cell 32:81–95. https://doi.org/10.1016/j.molcel.2008.08.008

    CAS  CrossRef  PubMed  Google Scholar 

  63. Nik S, Bowman TV (2019) Splicing and neurodegeneration: insights and mechanisms. Wiley Interdiscip Rev RNA 10:e1532

    PubMed  CrossRef  CAS  Google Scholar 

  64. Escobar-Hoyos L, Knorr K, Abdel-Wahab O (2019) Aberrant RNA splicing in cancer. Annu Rev Cancer Biol 3:167–185

    PubMed  CrossRef  Google Scholar 

  65. Orengo JP, Ward AJ, Cooper TA (2011) Alternative splicing dysregulation secondary to skeletal muscle regeneration. Ann Neurol 69:681–690. https://doi.org/10.1002/ana.22278

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  66. Faustino NA, Cooper TA (2003) Pre-mRNA splicing and human disease. Genes Dev 17:419–437

    CAS  PubMed  CrossRef  Google Scholar 

  67. Pagani F, Baralle FE (2004) Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389–396

    CAS  PubMed  CrossRef  Google Scholar 

  68. Meola G, Cardani R (2015) Myotonic dystrophies: an update on clinical aspects, genetic, pathology, and molecular pathomechanisms. Biochim Biophys Acta Mol basis Dis 1852:594–606

    CAS  CrossRef  Google Scholar 

  69. Brook JD, McCurrach ME, Harley HG et al (1992) Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68:799–808. https://doi.org/10.1016/0092-8674(92)90154-5

    CAS  CrossRef  PubMed  Google Scholar 

  70. Fu YH, Pizzuti A, Fenwick RG et al (1992) An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255:1256–1258. https://doi.org/10.1126/science.1546326

    CAS  CrossRef  PubMed  Google Scholar 

  71. Mahadevan M, Tsilfidis C, Sabourin L et al (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255:1253–1255. https://doi.org/10.1126/science.1546325

    CAS  CrossRef  PubMed  Google Scholar 

  72. Davis BM, Mccurrach ME, Taneja KL et al (1997) Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc Natl Acad Sci U S A 94:7388–7393. https://doi.org/10.1073/pnas.94.14.7388

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  73. Miller JW, Urbinati CR, Teng-Umnuay P et al (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19:4439–4448. https://doi.org/10.1093/emboj/19.17.4439

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  74. Kuyumcu-Martinez NM, Wang GS, Cooper TA (2007) Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell 28:68–78. https://doi.org/10.1016/j.molcel.2007.07.027

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  75. Kalsotra A, Xiao X, Ward AJ et al (2008) A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc Natl Acad Sci U S A 105:20333–20338. https://doi.org/10.1073/pnas.0809045105

    CrossRef  PubMed  PubMed Central  Google Scholar 

  76. Ladd AN, Charlet-B N, Cooper TA (2001) The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol Cell Biol 21:1285–1296. https://doi.org/10.1128/mcb.21.4.1285-1296.2001

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  77. Charizanis K, Lee KY, Batra R et al (2012) Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. Neuron 75:437–450. https://doi.org/10.1016/j.neuron.2012.05.029

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  78. Charlet BN, Savkur RS, Singh G et al (2002) Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell 10:45–53. https://doi.org/10.1016/S1097-2765(02)00572-5

    CrossRef  Google Scholar 

  79. Mankodi A, Takahashi MP, Jiang H et al (2002) Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 10:35–44. https://doi.org/10.1016/S1097-2765(02)00563-4

    CAS  CrossRef  PubMed  Google Scholar 

  80. Savkur RS, Philips AV, Cooper TA (2001) Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet 29:40–47. https://doi.org/10.1038/ng704

    CAS  CrossRef  PubMed  Google Scholar 

  81. Philips AV, Timchenko LT, Cooper TA (1998) Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280:737–741. https://doi.org/10.1126/science.280.5364.737

    CAS  CrossRef  PubMed  Google Scholar 

  82. Sergeant N, Sablonnière B, Schraen-Maschke S et al (2001) Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet 10:2143–2155. https://doi.org/10.1093/hmg/10.19.2143

    CAS  CrossRef  PubMed  Google Scholar 

  83. Lunn MR, Wang CH (2008) Spinal muscular atrophy. Lancet 371:2120–2133

    PubMed  CrossRef  Google Scholar 

  84. Lefebvre S, Bürglen L, Reboullet S et al (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155–165. https://doi.org/10.1016/0092-8674(95)90460-3

    CAS  CrossRef  PubMed  Google Scholar 

  85. Schrank B, Götz R, Gunnersen JM et al (1997) Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci U S A 94:9920–9925. https://doi.org/10.1073/pnas.94.18.9920

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  86. Cartegni L, Krainer AR (2002) Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN. Nat Genet 30:377–384. https://doi.org/10.1038/ng854

    CAS  CrossRef  PubMed  Google Scholar 

  87. Kashima T, Manley JL (2003) A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat Genet 34:460–463. https://doi.org/10.1038/ng1207

    CAS  CrossRef  PubMed  Google Scholar 

  88. Singh NN, Androphy EJ, Singh RN (2004) In vivo selection reveals combinatorial controls that define a critical exon in the spinal muscular atrophy genes. RNA 10:1291–1305. https://doi.org/10.1261/rna.7580704

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  89. Burnett BG, Muñoz E, Tandon A et al (2009) Regulation of SMN protein stability. Mol Cell Biol 29:1107–1115. https://doi.org/10.1128/mcb.01262-08

    CAS  CrossRef  PubMed  Google Scholar 

  90. Meister G, Bühler D, Pillai R et al (2001) A multiprotein complex mediates the ATP-dependent assembly of spliceosomal U snRNPs. Nat Cell Biol 3:945–949. https://doi.org/10.1038/ncb1101-945

    CAS  CrossRef  PubMed  Google Scholar 

  91. Pellizzoni L, Yong J, Dreyfuss G (2002) Essential role for the SMN complex in the specificity of snRNP assembly. Science 298:1775–1779. https://doi.org/10.1126/science.1074962

    CAS  CrossRef  PubMed  Google Scholar 

  92. Neuenkirchen N, Englbrecht C, Ohmer J et al (2015) Reconstitution of the human U sn RNP assembly machinery reveals stepwise Sm protein organization. EMBO J 34:1925–1941. https://doi.org/10.15252/embj.201490350

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  93. Ruggiu M, McGovern VL, Lotti F et al (2012) A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy. Mol Cell Biol 32:126–138. https://doi.org/10.1128/mcb.06077-11

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  94. Zhang Z, Lotti F, Dittmar K et al (2008) SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell 133:585–600. https://doi.org/10.1016/j.cell.2008.03.031

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  95. Workman E, Saieva L, Carrel TL et al (2009) A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice. Hum Mol Genet 18:2215–2229. https://doi.org/10.1093/hmg/ddp157

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  96. Gabanella F, Butchbach MER, Saieva L et al (2007) Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS One 2:e921. https://doi.org/10.1371/journal.pone.0000921

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  97. Doktor TK, Hua Y, Andersen HS et al (2017) RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns. Nucleic Acids Res 45:395–416. https://doi.org/10.1093/nar/gkw731

    CAS  CrossRef  PubMed  Google Scholar 

  98. Osman EY, van Alstyne M, Yen PF et al (2020) Minor snRNA gene delivery improves the loss of proprioceptive synapses on SMA motor neurons. JCI Insight 5:e130574. https://doi.org/10.1172/jci.insight.130574

    CrossRef  PubMed Central  Google Scholar 

  99. Lotti F, Imlach WL, Saieva L et al (2012) An SMN-dependent U12 splicing event essential for motor circuit function. Cell 151:440–454. https://doi.org/10.1016/j.cell.2012.09.012

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  100. Simon CM, Van Alstyne M, Lotti F et al (2019) Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy. Cell Rep 29:3885–3901.e5. https://doi.org/10.1016/j.celrep.2019.11.058

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  101. Simon CM, Dai Y, Van Alstyne M et al (2017) Converging mechanisms of p53 activation drive motor neuron degeneration in spinal muscular atrophy. Cell Rep 21:3767–3780. https://doi.org/10.1016/j.celrep.2017.12.003

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  102. Van Alstyne M, Simon CM, Sardi SP et al (2018) Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy. Genes Dev 32:1045–1059. https://doi.org/10.1101/gad.316059.118

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  103. Pagliardini S, Giavazzi A, Setola V et al (2000) Subcellular localization and axonal transport of the survival motor neuron (SMN) protein in the developing rat spinal cord. Hum Mol Genet 9:47–56. https://doi.org/10.1093/hmg/9.1.47

    CAS  CrossRef  PubMed  Google Scholar 

  104. Kye MJ, Niederst ED, Wertz MH et al (2014) SMN regulates axonal local translation via miR-183/mTOR pathway. Hum Mol Genet 23:6318–6331. https://doi.org/10.1093/hmg/ddu350

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  105. Kiernan MC, Vucic S, Cheah BC et al (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955

    CAS  PubMed  CrossRef  Google Scholar 

  106. Rowland LP, Shneider NA (2001) Medical Progress. Amyotrophic lateral sclerosis. N Engl J Med 344:1688–1700

    Google Scholar 

  107. Mathis S, Goizet C, Soulages A et al (2019) Genetics of amyotrophic lateral sclerosis: a review. J Neurol Sci 399:217–226

    CAS  PubMed  CrossRef  Google Scholar 

  108. Renton AE, Chiò A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17–23

    CAS  PubMed  CrossRef  Google Scholar 

  109. Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in als and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  110. Tollervey JR, Curk T, Rogelj B et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458. https://doi.org/10.1038/nn.2778

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  111. Humphrey J, Emmett W, Fratta P et al (2017) Quantitative analysis of cryptic splicing associated with TDP-43 depletion. BMC Med Genet 10:38. https://doi.org/10.1186/s12920-017-0274-1

    CAS  CrossRef  Google Scholar 

  112. Ling JP, Pletnikova O, Troncoso JC, Wong PC (2015) TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349:650–655. https://doi.org/10.1126/science.aab0983

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  113. Tan Q, Yalamanchili HK, Park J et al (2016) Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. Hum Mol Genet 25:5083–5093. https://doi.org/10.1093/hmg/ddw337

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  114. Klim JR, Williams LA, Limone F et al (2019) ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat Neurosci 22:167–179. https://doi.org/10.1038/s41593-018-0300-4

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  115. Melamed Z, López-Erauskin J, Baughn MW et al (2019) Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci 22:180–190. https://doi.org/10.1038/s41593-018-0293-z

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  116. Chauvin S, Sobel A (2015) Neuronal stathmins: a family of phosphoproteins cooperating for neuronal development, plasticity and regeneration. Prog Neurobiol 126:1–18

    CAS  PubMed  CrossRef  Google Scholar 

  117. Ebstein SY, Yagudayeva I, Shneider NA (2019) Mutant TDP-43 causes early-stage dose-dependent motor neuron degeneration in a TARDBP Knockin mouse model of ALS. Cell Rep 26:364–373.e4. https://doi.org/10.1016/j.celrep.2018.12.045

    CAS  CrossRef  PubMed  Google Scholar 

  118. Mitchell JC, Constable R, So E et al (2015) Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS. Acta Neuropathol Commun 3:36. https://doi.org/10.1186/s40478-015-0212-4

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  119. Fratta P, Sivakumar P, Humphrey J et al (2018) Mice with endogenous TDP -43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis. EMBO J 37:e98684. https://doi.org/10.15252/embj.201798684

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  120. Vance C, Rogelj B, Hortobágyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211. https://doi.org/10.1126/science.1165942

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  121. Kwiatkowski TJ, Bosco DA, LeClerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208. https://doi.org/10.1126/science.1166066

    CAS  CrossRef  PubMed  Google Scholar 

  122. Dormann D, Rodde R, Edbauer D et al (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. EMBO J 29:2841–2857. https://doi.org/10.1038/emboj.2010.143

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  123. Loughlin FE, Lukavsky PJ, Kazeeva T et al (2019) The solution structure of FUS bound to RNA reveals a bipartite mode of RNA recognition with both sequence and shape specificity. Mol Cell 73:490–504.e6. https://doi.org/10.1016/j.molcel.2018.11.012

    CAS  CrossRef  PubMed  Google Scholar 

  124. Rogelj B, Easton LE, Bogu GK et al (2012) Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci Rep 2:603. https://doi.org/10.1038/srep00603

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  125. Lagier-Tourenne C, Polymenidou M, Hutt KR et al (2012) Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci 15:1488–1497. https://doi.org/10.1038/nn.3230

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  126. Devoy A, Kalmar B, Stewart M et al (2017) Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in “FUSDelta14” knockin mice. Brain 140:2797–2805. https://doi.org/10.1093/brain/awx248

    CrossRef  PubMed  PubMed Central  Google Scholar 

  127. Scekic-Zahirovic J, Sendscheid O, El Oussini H et al (2016) Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. EMBO J 35:1077–1097. https://doi.org/10.15252/embj.201592559

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  128. Gerbino V, Carrì MT, Cozzolino M, Achsel T (2013) Mislocalised FUS mutants stall spliceosomal snRNPs in the cytoplasm. Neurobiol Dis 55:120–128. https://doi.org/10.1016/j.nbd.2013.03.003

    CAS  CrossRef  PubMed  Google Scholar 

  129. Sun S, Ling SC, Qiu J et al (2015) ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat Commun 6:6171. https://doi.org/10.1038/ncomms7171

    CAS  CrossRef  PubMed  Google Scholar 

  130. Yu Y, Chi B, Xia W et al (2015) U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish. Nucleic Acids Res 43:3208–3218. https://doi.org/10.1093/nar/gkv157

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  131. Panza F, Lozupone M, Seripa D et al (2020) Development of disease-modifying drugs for frontotemporal dementia spectrum disorders. Nat Rev Neurol 16:213–228

    CAS  PubMed  CrossRef  Google Scholar 

  132. Hodges JR, Piguet O (2018) Progress and challenges in frontotemporal dementia research: a 20-year review. J Alzheimers Dis 62:1467–1480

    PubMed  PubMed Central  CrossRef  Google Scholar 

  133. Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–704. https://doi.org/10.1038/31508

    CAS  CrossRef  PubMed  Google Scholar 

  134. Wszolek ZK, Tsuboi Y, Ghetti B et al (2006) Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Orphanet J Rare Dis 1:30

    PubMed  PubMed Central  CrossRef  Google Scholar 

  135. Ehrlich M, Hallmann AL, Reinhardt P et al (2015) Distinct neurodegenerative changes in an induced pluripotent stem cell model of frontotemporal dementia linked to mutant TAU protein. Stem Cell Rep 5:83–96. https://doi.org/10.1016/j.stemcr.2015.06.001

    CAS  CrossRef  Google Scholar 

  136. D’Souza I, Schellenberg GD (2005) Regulation of tau isoform expression and dementia. Biochim Biophys Acta Mol basis Dis 1739:104–115

    CrossRef  CAS  Google Scholar 

  137. Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133:665–704

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  138. Niblock M, Gallo JM (2012) Tau alternative splicing in familial and sporadic tauopathies. Biochem Soc Trans 40:677–680

    CAS  PubMed  CrossRef  Google Scholar 

  139. Wolfe MS (2012) The role of tau in neurodegenerative diseases and its potential as a therapeutic target. Scientifica (Cairo) 2012:1–20. https://doi.org/10.6064/2012/796024

    CrossRef  Google Scholar 

  140. Grover A, Houlden H, Baker M et al (1999) 5′ splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem 274:15134–15143. https://doi.org/10.1074/jbc.274.21.15134

    CAS  CrossRef  PubMed  Google Scholar 

  141. Andreadis A (2012) Tau splicing and the intricacies of dementia. J Cell Physiol 227:1220–1225

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  142. Kar A, Havlioglu N, Tarn WY, Wu JY (2006) RBM4 interacts with an intronic element and stimulates tau exon 10 inclusion. J Biol Chem 281:24479–24488. https://doi.org/10.1074/jbc.M603971200

    CAS  CrossRef  PubMed  Google Scholar 

  143. Chapple PJ, Anthony K, Martin TR et al (2007) Expression, localization and tau exon 10 splicing activity of the brain RNA-binding protein TNRC4. Hum Mol Genet 16:2760–2769. https://doi.org/10.1093/hmg/ddm233

    CAS  CrossRef  PubMed  Google Scholar 

  144. Gao L, Wang J, Wang Y, Andreadis A (2007) SR protein 9G8 modulates splicing of tau exon 10 via its proximal downstream intron, a clustering region for frontotemporal dementia mutations. Mol Cell Neurosci 34:48–58. https://doi.org/10.1016/j.mcn.2006.10.004

    CAS  CrossRef  PubMed  Google Scholar 

  145. Kar A, Fushimi K, Zhou X et al (2011) RNA helicase p68 (DDX5) regulates tau exon 10 splicing by modulating a stem-loop structure at the 5’ splice site. Mol Cell Biol 31:1812–1821. https://doi.org/10.1128/mcb.01149-10

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  146. Kondo S, Yamamoto N, Murakami T et al (2004) Tra2β, SF2/ASF and SRp30c modulate the function of an exonic splicing enhancer in exon 10 of tau pre-mRNA. Genes Cells 9:121–130. https://doi.org/10.1111/j.1356-9597.2004.00709.x

    CAS  CrossRef  PubMed  Google Scholar 

  147. Strang KH, Golde TE, Giasson BI (2019) MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Investig 99:912–928

    PubMed  CrossRef  Google Scholar 

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Acknowledgments

This work was supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd., funded by the Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK.

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Jutzi, D., Ruepp, MD. (2022). Alternative Splicing in Human Biology and Disease. In: Scheiffele, P., Mauger, O. (eds) Alternative Splicing. Methods in Molecular Biology, vol 2537. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2521-7_1

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