RNP Assembly Defects in Spinal Muscular Atrophy

  • Phillip L. Price
  • Dmytro Morderer
  • Wilfried RossollEmail author
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 20)


Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations/deletions within the survival of motor neuron 1 (SMN1) gene that lead to a pathological reduction of SMN protein levels. SMN is part of a multiprotein complex, functioning as a molecular chaperone that facilitates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNP). In addition to its role in spliceosome formation, SMN has also been found to interact with mRNA-binding proteins (mRBPs), and facilitate their assembly into mRNP transport granules. The association of protein and RNA in RNP complexes plays an important role in an extensive and diverse set of cellular processes that regulate neuronal growth, differentiation, and the maturation and plasticity of synapses. This review discusses the role of SMN in RNP assembly and localization, focusing on molecular defects that affect mRNA processing and may contribute to SMA pathology.


Spinal muscular atrophy (SMA) Survival of motor neuron (SMN) RNA-binding protein (RBP) Ribonucleoprotein (RNP) Molecular chaperone RNA processing RNA localization 


  1. 1.
    Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011;68(8):979–84.PubMedCrossRefGoogle Scholar
  2. 2.
    Prior TW, Snyder PJ, Rink BD, Pearl DK, Pyatt RE, Mihal DC, et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A. 2010;152A(7):1608–16.PubMedCrossRefGoogle Scholar
  3. 3.
    Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis. 2017;12(1):124.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Zerres K, Wirth B, Rudnik-Schöneborn S. Spinal muscular atrophy—clinical and genetic correlations. Neuromuscul Disord. 1997;7(3):202–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–65.CrossRefPubMedGoogle Scholar
  6. 6.
    McAndrew PE, Parsons DW, Simard LR, Rochette C, Ray PN, Mendell JR, et al. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am J Hum Genet. 1997;60(6):1411–22.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Campbell L, Potter A, Ignatius J, Dubowitz V, Davies K. Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype. Am J Hum Genet. 1997;61(1):40–50.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal-neurons and adult-astrocytes in CNS. Nat Biotechnol. 2009;27(1):59–65.PubMedCrossRefGoogle Scholar
  9. 9.
    Naryshkin NA, Weetall M, Dakka A, Narasimhan J, Zhao X, Feng Z, et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science (New York, NY). 2014;345(6197):688–93.CrossRefGoogle Scholar
  10. 10.
    Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010;24(15):1634–44.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Rigo F, Chun SJ, Norris DA, Hung G, Lee S, Matson J, et al. Pharmacology of a central nervous system delivered 2′-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. J Pharmacol Exp Ther. 2014;350(1):46–55.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Singh NN, Howell MD, Androphy EJ, Singh RN. How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther. 2017;24(9):520–6.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Hoy SM. Nusinersen: first global approval. Drugs. 2017;77(4):473–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Burgart AM, Magnus D, Tabor HK, Paquette ED, Frader J, Glover JJ, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188–92.PubMedCrossRefGoogle Scholar
  15. 15.
    Day M, Wang Z, Ding J, An X, Ingham CA, Shering AF, et al. Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nat Neurosci. 2006;9(2):251–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008;14(8):837–42.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004;185(2):232–40.PubMedCrossRefGoogle Scholar
  18. 18.
    Edens BM, Ajroud-Driss S, Ma L, Ma Y-C. Molecular mechanisms and animal models of spinal muscular atrophy. Biochim Biophys Acta Mol Basis Dis. 2015;1852(4):685–92.CrossRefGoogle Scholar
  19. 19.
    Schrank B, Gotz R, Gunnersen JM, Ure JM, Toyka KV, Smith AG, et al. 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. 1997;94(18):9920–5.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C, Le TT, et al. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(−/−) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet. 2000;9(3):333–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Hsieh-Li HM, Chang JG, Jong YJ, Wu MH, Wang NM, Tsai CH, et al. A mouse model for spinal muscular atrophy. Nat Genet. 2000;24(1):66–70.PubMedCrossRefGoogle Scholar
  22. 22.
    Le TT, Pham LT, Butchbach ME, Zhang HL, Monani UR, Coovert DD, et al. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet. 2005;14(6):845–57.PubMedCrossRefGoogle Scholar
  23. 23.
    Bowerman M, Murray LM, Beauvais A, Pinheiro B, Kothary R. A critical smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology. Neuromuscul Disord. 2012;22(3):263–76.PubMedCrossRefGoogle Scholar
  24. 24.
    Hammond SM, Gogliotti RG, Rao V, Beauvais A, Kothary R, DiDonato CJ. Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late. PLoS One. 2010;5(12):e15887.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Cifuentes-Diaz C, Nicole S, Velasco ME, Borra-Cebrian C, Panozzo C, Frugier T, et al. Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model. Hum Mol Genet. 2002;11(12):1439–47.PubMedCrossRefGoogle Scholar
  26. 26.
    Xu CC, Denton KR, Wang ZB, Zhang X, Li XJ. Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy. Dis Model Mech. 2016;9(1):39–49.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Miller N, Shi H, Zelikovich AS, Ma Y-C. Motor neuron mitochondrial dysfunction in spinal muscular atrophy. Hum Mol Genet. 2016;25(16):3395–406.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Kariya S, Park GH, Maeno-Hikichi Y, Leykekhman O, Lutz C, Arkovitz MS, et al. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum Mol Genet. 2008;17(16):2552–69.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kong L, Wang X, Choe DW, Polley M, Burnett BG, Bosch-Marce M, et al. Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice. J Neurosci. 2009;29(3):842–51.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Martinez-Hernandez R, Bernal S, Also-Rallo E, Alias L, Barcelo MJ, Hereu M, et al. Synaptic defects in type I spinal muscular atrophy in human development. J Pathol. 2013;229(1):49–61.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Diers A, Kaczinski M, Grohmann K, Hubner C, Stoltenburg-Didinger G. The ultrastructure of peripheral nerve, motor end-plate and skeletal muscle in patients suffering from spinal muscular atrophy with respiratory distress type 1 (SMARD1). Acta Neuropathol. 2005;110(3):289–97.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Martinez-Hernandez R, Soler-Botija C, Also E, Alias L, Caselles L, Gich I, et al. The developmental pattern of myotubes in spinal muscular atrophy indicates prenatal delay of muscle maturation. J Neuropathol Exp Neurol. 2009;68(5):474–81.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Lee YI, Mikesh M, Smith I, Rimer M, Thompson W. Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons. Dev Biol. 2011;356(2):432–44.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Hayhurst M, Wagner AK, Cerletti M, Wagers AJ, Rubin LL. A cell-autonomous defect in skeletal muscle satellite cells expressing low levels of survival of motor neuron protein. Dev Biol. 2012;368(2):323–34.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Kim JK, Caine C, Awano T, Herbst R, Monani UR. Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice. Hum Mol Genet. 2017;26(13):2377–85.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Boido M, Vercelli A. Neuromuscular junctions as key contributors and therapeutic targets in spinal muscular atrophy. Front Neuroanat. 2016;10:6.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ling KKY, Lin M-Y, Zingg B, Feng Z, Ko C-P. Synaptic defects in the spinal and neuromuscular circuitry in a mouse model of spinal muscular atrophy. PLoS One. 2010;5(11):e15457.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Mentis GZ, Blivis D, Liu W, Drobac E, Crowder ME, Kong L, et al. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron. 2011;69(3):453–67.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Rindt H, Feng Z, Mazzasette C, Glascock JJ, Valdivia D, Pyles N, et al. Astrocytes influence the severity of spinal muscular atrophy. Hum Mol Genet. 2015;24(14):4094–102.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Zhou C, Feng Z, Ko CP. Defects in motoneuron-astrocyte interactions in spinal muscular atrophy. J Neurosci. 2016;36(8):2543–53.PubMedCrossRefGoogle Scholar
  41. 41.
    McGivern JV, Patitucci TN, Nord JA, Barabas M-EA, Stucky CL, Ebert AD. Spinal muscular atrophy astrocytes exhibit abnormal calcium regulation and reduced growth factor production. Glia. 2013;61(9):1418–28.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hunter G, Aghamaleky Sarvestany A, Roche SL, Symes RC, Gillingwater TH. SMN-dependent intrinsic defects in Schwann cells in mouse models of spinal muscular atrophy. Hum Mol Genet. 2014;23(9):2235–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Martin JE, Nguyen TT, Grunseich C, Nofziger JH, Lee PR, Fields D, et al. Decreased motor neuron support by SMA astrocytes due to diminished MCP1 secretion. J Neurosci. 2017;37(21):5309–18.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Sison SL, Patitucci TN, Seminary ER, Villalon E, Lorson CL, Ebert AD. Astrocyte-produced miR-146a as a mediator of motor neuron loss in spinal muscular atrophy. Hum Mol Genet. 2017;26(17):3409–20.PubMedCrossRefGoogle Scholar
  45. 45.
    Gogliotti RG, Quinlan KA, Barlow CB, Heier CR, Heckman CJ, Didonato CJ. Motor neuron rescue in spinal muscular atrophy mice demonstrates that sensory-motor defects are a consequence, not a cause, of motor neuron dysfunction. J Neurosci. 2012;32(11):3818–29.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    McGovern VL, Iyer CC, Arnold WD, Gombash SE, Zaworski PG, Blatnik AJ, et al. SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNΔ7 mouse model of SMA. Hum Mol Genet. 2015;24(19):5524–41.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Gavrilina TO, McGovern VL, Workman E, Crawford TO, Gogliotti RG, DiDonato CJ, et al. Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum Mol Genet. 2008;17(8):1063–75.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Iyer CC, McGovern VL, Murray JD, Gombash SE, Zaworski PG, Foust KD, et al. Low levels of Survival Motor Neuron protein are sufficient for normal muscle function in the SMNDelta7 mouse model of SMA. Hum Mol Genet. 2015;24(21):6160–73.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Shababi M, Lorson CL, Rudnik-Schoneborn SS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2014;224(1):15–28.PubMedCrossRefGoogle Scholar
  50. 50.
    Nash LA, Burns JK, Chardon JW, Kothary R, Parks RJ. Spinal muscular atrophy: more than a disease of motor neurons? Curr Mol Med. 2016;16(9):779–92.CrossRefPubMedGoogle Scholar
  51. 51.
    Wirth B, Barkats M, Martinat C, Sendtner M, Gillingwater TH. Moving towards treatments for spinal muscular atrophy: hopes and limits. Expert Opin Emerg Drugs. 2015;20(3):353–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Burghes AHM, Beattie CE. Spinal muscular atrophy: why do low levels of SMN make motor neurons sick? Nat Rev Neurosci. 2009;10(8):597–609.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Jablonka S, Sendtner M. Developmental regulation of SMN expression: pathophysiological implications and perspectives for therapy development in spinal muscular atrophy. Gene Ther. 2017;24(9):506–13.PubMedCrossRefGoogle Scholar
  54. 54.
    Dombert B, Sivadasan R, Simon CM, Jablonka S, Sendtner M. Presynaptic localization of Smn and hnRNP R in axon terminals of embryonic and postnatal mouse motoneurons. PLoS One. 2014;9(10):e110846.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Fallini C, Donlin-Asp PG, Rouanet JP, Bassell GJ, Rossoll W. Deficiency of the survival of motor neuron protein impairs mRNA localization and local translation in the growth cone of motor neurons. J Neurosci. 2016;36(13):3811–20.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Hao le T, Duy PQ, Jontes JD, Beattie CE. Motoneuron development influences dorsal root ganglia survival and Schwann cell development in a vertebrate model of spinal muscular atrophy. Hum Mol Genet. 2015;24(2):346–60.PubMedCrossRefGoogle Scholar
  57. 57.
    Zhang HL, Pan F, Hong D, Shenoy SM, Singer RH, Bassell GJ. Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization. J Neurosci. 2003;23(16):6627–37.PubMedCrossRefGoogle Scholar
  58. 58.
    Fallini C, Bassell GJ, Rossoll W. High-efficiency transfection of cultured primary motor neurons to study protein localization, trafficking, and function. Mol Neurodegener. 2010;5:17.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Gruss OJ, Meduri R, Schilling M, Fischer U. UsnRNP biogenesis: mechanisms and regulation. Chromosoma. 2017;126(5):577–93.PubMedCrossRefGoogle Scholar
  60. 60.
    Li DK, Tisdale S, Lotti F, Pellizzoni L. SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease. Semin Cell Dev Biol. 2014;32:22–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Ramaswami M, Taylor JP, Parker R. Altered ribostasis: RNA-protein granules in degenerative disorders. Cell. 2013;154(4):727–36.PubMedCrossRefGoogle Scholar
  62. 62.
    Shukla S, Parker R. Hypo- and hyper-assembly diseases of RNA–protein complexes. Trends Mol Med. 2016;22(7):615–28.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Donlin-Asp PG, Fallini C, Campos J, Chou CC, Merritt ME, Phan HC, et al. The survival of motor neuron protein acts as a molecular chaperone for mRNP assembly. Cell Rep. 2017;18(7):1660–73.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Pellizzoni L. Chaperoning ribonucleoprotein biogenesis in health and disease. EMBO Rep. 2007;8(4):340–5.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Cauchi RJ. SMN and Gemins: ‘we are family’ ... or are we?: insights into the partnership between Gemins and the spinal muscular atrophy disease protein SMN. Bioessays. 2010;32(12):1077–89.PubMedCrossRefGoogle Scholar
  66. 66.
    Otter S, Grimmler M, Neuenkirchen N, Chari A, Sickmann A, Fischer U. A comprehensive interaction map of the human survival of motor neuron (SMN) complex. J Biol Chem. 2007;282(8):5825–33.PubMedCrossRefGoogle Scholar
  67. 67.
    Fischer U, Liu Q, Dreyfuss G. The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell. 1997;90(6):1023–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Meister G, Buhler D, Pillai R, Lottspeich F, Fischer U. A multiprotein complex mediates the ATP-dependent assembly of spliceosomal U snRNPs. Nat Cell Biol. 2001;3(11):945–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Pellizzoni L, Yong J, Dreyfuss G. Essential role for the SMN complex in the specificity of snRNP assembly. Science. 2002;298(5599):1775–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Brahms H, Meheus L, de Brabandere V, Fischer U, Luhrmann R. Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B′ and the Sm-like protein LSm4, and their interaction with the SMN protein. RNA. 2001;7(11):1531–42.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Friesen WJ, Massenet S, Paushkin S, Wyce A, Dreyfuss G. SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets. Mol Cell. 2001;7(5):1111–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Charroux B, Pellizzoni L, Perkinson RA, Shevchenko A, Mann M, Dreyfuss G. Gemin3: a novel DEAD box protein that interacts with SMN, the spinal muscular atrophy gene product, and is a component of gems. J Cell Biol. 1999;147(6):1181–94.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Battle DJ, Lau CK, Wan L, Deng H, Lotti F, Dreyfuss G. The Gemin5 protein of the SMN complex identifies snRNAs. Mol Cell. 2006;23(2):273–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Lau CK, Bachorik JL, Dreyfuss G. Gemin5-snRNA interaction reveals an RNA binding function for WD repeat domains. Nat Struct Mol Biol. 2009;16(5):486–91.PubMedCrossRefGoogle Scholar
  75. 75.
    Ma Y, Dostie J, Dreyfuss G, Van Duyne GD. The Gemin6-Gemin7 heterodimer from the survival of motor neurons complex has an Sm protein-like structure. Structure. 2005;13(6):883–92.PubMedCrossRefGoogle Scholar
  76. 76.
    Meister G, Eggert C, Fischer U. SMN-mediated assembly of RNPs: a complex story. Trends Cell Biol. 2002;12(10):472–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Friesen WJ, Paushkin S, Wyce A, Massenet S, Pesiridis GS, Van Duyne G, et al. The methylosome, a 20S complex containing JBP1 and pICln, produces dimethylarginine-modified Sm proteins. Mol Cell Biol. 2001;21(24):8289–300.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Meister G, Eggert C, Bühler D, Brahms H, Kambach C, Fischer U. Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln. Curr Biol. 2001;11(24):1990–4.PubMedCrossRefGoogle Scholar
  79. 79.
    Chari A, Golas MM, Klingenhäger M, Neuenkirchen N, Sander B, Englbrecht C, et al. An assembly chaperone collaborates with the SMN complex to generate spliceosomal SnRNPs. Cell. 2008;135(3):497–509.PubMedCrossRefGoogle Scholar
  80. 80.
    Paushkin S, Gubitz AK, Massenet S, Dreyfuss G. The SMN complex, an assemblyosome of ribonucleoproteins. Curr Opin Cell Biol. 2002;14(3):305–12.PubMedCrossRefGoogle Scholar
  81. 81.
    Wan L, Battle DJ, Yong J, Gubitz AK, Kolb SJ, Wang J, et al. The survival of motor neurons protein determines the capacity for snRNP assembly: biochemical deficiency in spinal muscular atrophy. Mol Cell Biol. 2005;25(13):5543–51.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Patel AA, Steitz JA. Splicing double: insights from the second spliceosome. Nat Rev Mol Cell Biol. 2003;4(12):960–70.PubMedCrossRefGoogle Scholar
  83. 83.
    Turunen JJ, Niemelä EH, Verma B, Frilander MJ. The significant other: splicing by the minor spliceosome. Wiley Interdiscip Rev RNA. 2013;4(1):61–76.PubMedCrossRefGoogle Scholar
  84. 84.
    Elsaid MF, Chalhoub N, Ben-Omran T, Kumar P, Kamel H, Ibrahim K, et al. Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia. Ann Neurol. 2017;81(1):68–78.PubMedCrossRefGoogle Scholar
  85. 85.
    Bacrot S, Doyard M, Huber C, Alibeu O, Feldhahn N, Lehalle D, et al. Mutations in SNRPB, encoding components of the core splicing machinery, cause cerebro-costo-mandibular syndrome. Hum Mutat. 2015;36(2):187–90.PubMedCrossRefGoogle Scholar
  86. 86.
    Singh RK, Cooper TA. Pre-mRNA splicing in disease and therapeutics. Trends Mol Med. 2012;18(8):472–82.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Marzluff WF, Wagner EJ, Duronio RJ. Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat Rev Genet. 2008;9(11):843–54.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Tisdale S, Lotti F, Saieva L, Van Meerbeke JP, Crawford TO, Sumner CJ, et al. SMN is essential for the biogenesis of U7 snRNP and 3′-end formation of histone mRNAs. Cell Rep. 2013;5(5).
  89. 89.
    Vindry C, Marnef A, Broomhead H, Twyffels L, Ozgur S, Stoecklin G, et al. Dual RNA processing roles of Pat1b via cytoplasmic Lsm1-7 and nuclear Lsm2-8 complexes. Cell Rep. 2017;20(5):1187–200.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Zhang Z, Lotti F, Dittmar K, Younis I, Wan L, Kasim M, et al. SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell. 2008;133(4):585–600.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Winkler C, Eggert C, Gradl D, Meister G, Giegerich M, Wedlich D, et al. Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy. Genes Dev. 2005;19(19):2320–30.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    McWhorter ML, Boon KL, Horan ES, Burghes AH, Beattie CE. The SMN binding protein Gemin2 is not involved in motor axon outgrowth. Dev Neurobiol. 2008;68(2):182–94.PubMedCrossRefGoogle Scholar
  93. 93.
    Gabanella F, Butchbach ME, Saieva L, Carissimi C, Burghes AH, Pellizzoni L. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS One. 2007;2(9):e921.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Lotti F, Imlach WL, Saieva L, Beck ES, Hao le T, Li DK, et al. An SMN-dependent U12 splicing event essential for motor circuit function. Cell. 2012;151(2):440–54.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Praveen K, Wen Y, Matera AG. A Drosophila model of spinal muscular atrophy uncouples snRNP biogenesis functions of survival motor neuron from locomotion and viability defects. Cell Rep. 2012;1(6):624–31.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Garcia EL, Wen Y, Praveen K, Matera AG. Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy. RNA (New York, NY). 2016;22(8):1215–27.CrossRefGoogle Scholar
  97. 97.
    Rajendra TK, Gonsalvez GB, Walker MP, Shpargel KB, Salz HK, Matera AG. A Drosophila melanogaster model of spinal muscular atrophy reveals a function for SMN in striated muscle. J Cell Biol. 2007;176(6):831–41.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Sauterer RA, Feeney RJ, Zieve GW. Cytoplasmic assembly of snRNP particles from stored proteins and newly transcribed snRNA’s in L929 mouse fibroblasts. Exp Cell Res. 1988;176(2):344–59.PubMedCrossRefGoogle Scholar
  99. 99.
    Fallini C, Bassell GJ, Rossoll W. Spinal muscular atrophy: the role of SMN in axonal mRNA regulation. Brain Res. 2012;1462:81–92.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Briese M, Esmaeili B, Sattelle DB. Is spinal muscular atrophy the result of defects in motor neuron processes? Bioessays. 2005;27(9):946–57.PubMedCrossRefGoogle Scholar
  101. 101.
    Donlin-Asp PG, Bassell GJ, Rossoll W. A role for the survival of motor neuron protein in mRNP assembly and transport. Curr Opin Neurobiol. 2016;39:53–61.PubMedCrossRefGoogle Scholar
  102. 102.
    Rossoll W, Bassell GJ. Spinal muscular atrophy and a model for survival of motor neuron protein function in axonal ribonucleoprotein complexes. Results Probl Cell Differ. 2009;48:289–326.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Fallini C, Zhang H, Su Y, Silani V, Singer RH, Rossoll W, et al. The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. J Neurosci. 2011;31(10):3914–25.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Rossoll W, Jablonka S, Andreassi C, Kroning AK, Karle K, Monani UR, et al. Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons. J Cell Biol. 2003;163(4):801–12.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Kye MJ, Niederst ED, Wertz MH, Goncalves Ido C, Akten B, Dover KZ, et al. SMN regulates axonal local translation via miR-183/mTOR pathway. Hum Mol Genet. 2014;23(23):6318–31.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Fallini C, Rouanet JP, Donlin-Asp PG, Guo P, Zhang H, Singer RH, et al. Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA-binding protein IMP1 facilitates its trafficking into motor neuron axons. Dev Neurobiol. 2014;74(3):319–32.PubMedCrossRefGoogle Scholar
  107. 107.
    Rossoll W, Kroning AK, Ohndorf UM, Steegborn C, Jablonka S, Sendtner M. Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons? Hum Mol Genet. 2002;11(1):93–105.PubMedCrossRefGoogle Scholar
  108. 108.
    Tadesse H, Deschenes-Furry J, Boisvenue S, Cote J. KH-type splicing regulatory protein interacts with survival motor neuron protein and is misregulated in spinal muscular atrophy. Hum Mol Genet. 2008;17(4):506–24.PubMedCrossRefGoogle Scholar
  109. 109.
    Akten B, Kye MJ, Hao le T, Wertz MH, Singh S, Nie D, et al. Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. Proc Natl Acad Sci U S A. 2011;108(25):10337–42.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Wu KY, Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, et al. Local translation of RhoA regulates growth cone collapse. Nature. 2005;436(7053):1020–4.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Campbell DS, Holt CE. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron. 2001;32(6):1013–26.PubMedCrossRefGoogle Scholar
  112. 112.
    Leung KM, van Horck FP, Lin AC, Allison R, Standart N, Holt CE. Asymmetrical beta-actin mRNA translation in growth cones mediates attractive turning to netrin-1. Nat Neurosci. 2006;9(10):1247–56.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Shigeoka T, Jung H, Jung J, Turner-Bridger B, Ohk J, Lin Julie Q, et al. Dynamic axonal translation in developing and mature visual circuits. Cell. 2016;166(1):181–92.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Wong HH, Lin JQ, Strohl F, Roque CG, Cioni JM, Cagnetta R, et al. RNA docking and local translation regulate site-specific axon remodeling in vivo. Neuron. 2017;95(4):852–68 e8.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Andreassi C, Riccio A. To localize or not to localize: mRNA fate is in 3′UTR ends. Trends Cell Biol. 2009;19(9):465–74.PubMedCrossRefGoogle Scholar
  116. 116.
    Berkovits BD, Mayr C. Alternative 3′ UTRs act as scaffolds to regulate membrane protein localization. Nature. 2015;522(7556):363–7.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Kiebler MA, Bassell GJ. Neuronal RNA granules: movers and makers. Neuron. 2006;51(6):685–90.PubMedCrossRefGoogle Scholar
  118. 118.
    Vuppalanchi D, Coleman J, Yoo S, Merianda TT, Yadhati AG, Hossain J, et al. Conserved 3′-untranslated region sequences direct subcellular localization of chaperone protein mRNAs in neurons. J Biol Chem. 2010;285(23):18025–38.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. EMBO J. 1996;15(14):3555–65.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Pagliardini S, Giavazzi A, Setola V, Lizier C, Di Luca M, DeBiasi S, et al. Subcellular localization and axonal transport of the survival motor neuron (SMN) protein in the developing rat spinal cord. Hum Mol Genet. 2000;9(1):47–56.PubMedCrossRefGoogle Scholar
  121. 121.
    Jablonka S, Bandilla M, Wiese S, Buhler D, Wirth B, Sendtner M, et al. Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy. Hum Mol Genet. 2001;10(5):497–505.PubMedCrossRefGoogle Scholar
  122. 122.
    McWhorter ML, Monani UR, Burghes AH, Beattie CE. Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding. J Cell Biol. 2003;162(5):919–31.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Ymlahi-Ouazzani Q, O JB, Paillard E, Ballagny C, Chesneau A, Jadaud A, et al. Reduced levels of survival motor neuron protein leads to aberrant motoneuron growth in a Xenopus model of muscular atrophy. Neurogenetics. 2010;11(1):27–40.PubMedCrossRefGoogle Scholar
  124. 124.
    van Bergeijk J, Rydel-Konecke K, Grothe C, Claus P. The spinal muscular atrophy gene product regulates neurite outgrowth: importance of the C terminus. FASEB J. 2007;21(7):1492–502.PubMedCrossRefGoogle Scholar
  125. 125.
    Zhang H, Xing L, Rossoll W, Wichterle H, Singer RH, Bassell GJ. Multiprotein complexes of the survival of motor neuron protein SMN with Gemins traffic to neuronal processes and growth cones of motor neurons. J Neurosci. 2006;26(33):8622–32.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Todd AG, Morse R, Shaw DJ, Stebbings H, Young PJ. Analysis of SMN-neurite granules: core Cajal body components are absent from SMN-cytoplasmic complexes. Biochem Biophys Res Commun. 2010;397(3):479–85.PubMedCrossRefGoogle Scholar
  127. 127.
    Saal L, Briese M, Kneitz S, Glinka M, Sendtner M. Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation. RNA. 2014;20(11):1789–802.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Rage F, Boulisfane N, Rihan K, Neel H, Gostan T, Bertrand E, et al. Genome-wide identification of mRNAs associated with the protein SMN whose depletion decreases their axonal localization. RNA. 2013;19(12):1755–66.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Castello A, Fischer B, Frese Christian K, Horos R, Alleaume A-M, Foehr S, et al. Comprehensive identification of RNA-binding domains in human cells. Mol Cell. 2016;63(4):696–710.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Mourelatos Z, Abel L, Yong J, Kataoka N, Dreyfuss G. SMN interacts with a novel family of hnRNP and spliceosomal proteins. EMBO J. 2001;20(19):5443–52.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Piazzon N, Rage F, Schlotter F, Moine H, Branlant C, Massenet S. In vitro and in cellulo evidences for association of the survival of motor neuron complex with the fragile X mental retardation protein. J Biol Chem. 2008;283(9):5598–610.PubMedCrossRefGoogle Scholar
  132. 132.
    Hubers L, Valderrama-Carvajal H, Laframboise J, Timbers J, Sanchez G, Cote J. HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects. Hum Mol Genet. 2011;20(3):553–79.PubMedCrossRefGoogle Scholar
  133. 133.
    Wang IF, Reddy NM, Shen CK. Higher order arrangement of the eukaryotic nuclear bodies. Proc Natl Acad Sci U S A. 2002;99(21):13583–8.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Yamazaki T, Chen S, Yu Y, Yan B, Haertlein TC, Carrasco MA, et al. FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep. 2012;2(4):799–806.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Gribling-Burrer AS, Leichter M, Wurth L, Huttin A, Schlotter F, Troffer-Charlier N, et al. SECIS-binding protein 2 interacts with the SMN complex and the methylosome for selenoprotein mRNP assembly and translation. Nucleic Acids Res. 2017;45(9):5399–413.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Hao LT, Duy PQ, An M, Talbot J, Iyer CC, Wolman M, et al. HuD and the Survival Motor Neuron protein interact in motoneurons and are essential for motoneuron development, function and mRNA regulation. J Neurosci. 2017;37(48):11559–71.CrossRefGoogle Scholar
  137. 137.
    Glinka M, Herrmann T, Funk N, Havlicek S, Rossoll W, Winkler C, et al. The heterogeneous nuclear ribonucleoprotein-R is necessary for axonal beta-actin mRNA translocation in spinal motor neurons. Hum Mol Genet. 2010;19(10):1951–66.PubMedCrossRefGoogle Scholar
  138. 138.
    Jablonka S, Beck M, Lechner BD, Mayer C, Sendtner M. Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy. J Cell Biol. 2007;179(1):139–49.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Zappulo A, van den Bruck D, Ciolli Mattioli C, Franke V, Imami K, McShane E, et al. RNA localization is a key determinant of neurite-enriched proteome. Nat Commun. 2017;8(1):583.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Yao J, Sasaki Y, Wen Z, Bassell GJ, Zheng JQ. An essential role for beta-actin mRNA localization and translation in Ca2+-dependent growth cone guidance. Nat Neurosci. 2006;9(10):1265–73.PubMedCrossRefGoogle Scholar
  141. 141.
    Yoo S, Kim HH, Kim P, Donnelly CJ, Kalinski AL, Vuppalanchi D, et al. A HuD-ZBP1 ribonucleoprotein complex localizes GAP-43 mRNA into axons through its 3′ untranslated region AU-rich regulatory element. J Neurochem. 2013;126(6):792–804.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Donnelly CJ, Park M, Spillane M, Yoo S, Pacheco A, Gomes C, et al. Axonally synthesized β-actin and GAP-43 proteins support distinct modes of axonal growth. J Neurosci. 2013;33(8):3311–22.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Fujino T, Leslie JH, Eavri R, Chen JL, Lin WC, Flanders GH, et al. CPG15 regulates synapse stability in the developing and adult brain. Genes Dev. 2011;25(24):2674–85.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Donnelly CJ, Willis DE, Xu M, Tep C, Jiang C, Yoo S, et al. Limited availability of ZBP1 restricts axonal mRNA localization and nerve regeneration capacity. EMBO J. 2011;30(22):4665–77.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Gomes C, Lee SJ, Gardiner AS, Smith T, Sahoo PK, Patel P, et al. Axonal localization of neuritin/CPG15 mRNA is limited by competition for HuD binding. J Cell Sci. 2017;130(21):3650–62.PubMedCrossRefGoogle Scholar
  146. 146.
    Beckel-Mitchener AC, Miera A, Keller R, Perrone-Bizzozero NI. Poly(A) tail length-dependent stabilization of GAP-43 mRNA by the RNA-binding protein HuD. J Biol Chem. 2002;277(31):27996–8002.PubMedCrossRefGoogle Scholar
  147. 147.
    Bird CW, Gardiner AS, Bolognani F, Tanner DC, Chen C-Y, Lin W-J, et al. KSRP modulation of GAP-43 mRNA stability restricts axonal outgrowth in embryonic hippocampal neurons. PLoS One. 2013;8(11):e79255.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Sheinberger J, Shav-Tal Y. mRNPs meet stress granules. FEBS Lett. 2017;591(17):2534–42.PubMedCrossRefGoogle Scholar
  149. 149.
    Hua Y, Zhou J. Survival motor neuron protein facilitates assembly of stress granules. FEBS Lett. 2004;572(1–3):69–74.PubMedCrossRefGoogle Scholar
  150. 150.
    Zou T, Yang X, Pan D, Huang J, Sahin M, Zhou J. SMN deficiency reduces cellular ability to form stress granules, sensitizing cells to stress. Cell Mol Neurobiol. 2011;31(4):541–50.PubMedCrossRefGoogle Scholar
  151. 151.
    Arimoto K, Fukuda H, Imajoh-Ohmi S, Saito H, Takekawa M. Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat Cell Biol. 2008;10(11):1324–32.PubMedCrossRefGoogle Scholar
  152. 152.
    Thedieck K, Holzwarth B, Prentzell MT, Boehlke C, Klasener K, Ruf S, et al. Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells. Cell. 2013;154(4):859–74.PubMedCrossRefGoogle Scholar
  153. 153.
    Gallotta I, Mazzarella N, Donato A, Esposito A, Chaplin JC, Castro S, et al. Neuron-specific knock-down of SMN1 causes neuron degeneration and death through an apoptotic mechanism. Hum Mol Genet. 2016;25(12):2564–77.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Strasswimmer J, Lorson CL, Breiding DE, Chen JJ, Le T, Burghes AH, et al. Identification of survival motor neuron as a transcriptional activator-binding protein. Hum Mol Genet. 1999;8(7):1219–26.PubMedCrossRefGoogle Scholar
  155. 155.
    Young PJ, Day PM, Zhou J, Androphy EJ, Morris GE, Lorson CL. A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy. J Biol Chem. 2002;277(4):2852–9.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Zou J, Barahmand-Pour F, Blackburn ML, Matsui Y, Chansky HA, Yang L. Survival motor neuron (SMN) protein interacts with transcription corepressor mSin3A. J Biol Chem. 2004;279(15):14922–8.PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Pellizzoni L, Charroux B, Rappsilber J, Mann M, Dreyfuss G. A functional interaction between the survival motor neuron complex and RNA polymerase II. J Cell Biol. 2001;152(1):75–85.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Suraweera A, Lim Y, Woods R, Birrell GW, Nasim T, Becherel OJ, et al. Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation. Hum Mol Genet. 2009;18(18):3384–96.CrossRefPubMedGoogle Scholar
  159. 159.
    Zhao DY, Gish G, Braunschweig U, Li Y, Ni Z, Schmitges FW, et al. SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination. Nature. 2016;529(7584):48–53.PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Jangi M, Fleet C, Cullen P, Gupta SV, Mekhoubad S, Chiao E, et al. SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage. Proc Natl Acad Sci U S A. 2017;114(12):E2347–E56.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Rudnik-Schoneborn S, Arning L, Epplen JT, Zerres K. SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy. Neuromuscul Disord. 2012;22(3):258–62.CrossRefPubMedGoogle Scholar
  162. 162.
    Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004;74(6):1128–35.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Moreira MC, Klur S, Watanabe M, Nemeth AH, Le Ber I, Moniz JC, et al. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet. 2004;36(3):225–7.CrossRefPubMedGoogle Scholar
  164. 164.
    Salvi JS, Mekhail K. R-loops highlight the nucleus in ALS. Nucleus. 2015;6(1):23–9.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Gama-Carvalho M, L Garcia-Vaquero M, R Pinto F, Besse F, Weis J, Voigt A, et al. Linking amyotrophic lateral sclerosis and spinal muscular atrophy through RNA-transcriptome homeostasis: a genomics perspective. J Neurochem. 2017;141(1):12–30.PubMedCrossRefGoogle Scholar
  166. 166.
    Rathod R, Havlicek S, Frank N, Blum R, Sendtner M. Laminin induced local axonal translation of beta-actin mRNA is impaired in SMN-deficient motoneurons. Histochem Cell Biol. 2012;138(5):737–48.PubMedCrossRefGoogle Scholar
  167. 167.
    Sanchez G, Dury AY, Murray LM, Biondi O, Tadesse H, El Fatimy R, et al. A novel function for the survival motoneuron protein as a translational regulator. Hum Mol Genet. 2013;22(4):668–84.PubMedCrossRefGoogle Scholar
  168. 168.
    Gabanella F, Pisani C, Borreca A, Farioli-Vecchioli S, Ciotti MT, Ingegnere T, et al. SMN affects membrane remodelling and anchoring of the protein synthesis machinery. J Cell Sci. 2016;129(4):804–16.PubMedCrossRefGoogle Scholar
  169. 169.
    Bernabò P, Tebaldi T, Groen EJN, Lane FM, Perenthaler E, Mattedi F, et al. In vivo translatome profiling in spinal muscular atrophy reveals a role for SMN protein in ribosome biology. Cell Rep. 2017;21(4):953–65.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Donlin-Asp PG, Rossoll W, Bassell GJ. Spatially and temporally regulating translation via mRNA-binding proteins in cellular and neuronal function. FEBS Lett. 2017;591(11):1508–25.PubMedCrossRefGoogle Scholar
  171. 171.
    Costa CJ, Willis DE. To the end of the line: axonal mRNA transport and local translation in health and neurodegenerative disease. Dev Neurobiol. 2018;78(3):209–20.PubMedCrossRefGoogle Scholar
  172. 172.
    Batista AF, Hengst U. Intra-axonal protein synthesis in development and beyond. Int J Dev Neurosci. 2016;55:140–9.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Coyne AN, Zaepfel BL, Zarnescu DC. Failure to deliver and translate-new insights into RNA dysregulation in ALS. Front Cell Neurosci. 2017;11:243.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Hutten S, Sharangdhar T, Kiebler M. Unmasking the messenger. RNA Biol. 2014;11(8):992–7.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Jodelka FM, Ebert AD, Duelli DM, Hastings ML. A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2. Hum Mol Genet. 2010;19(24):4906–17.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    See K, Yadav P, Giegerich M, Cheong PS, Graf M, Vyas H, et al. SMN deficiency alters Nrxn2 expression and splicing in zebrafish and mouse models of spinal muscular atrophy. Hum Mol Genet. 2014;23(7):1754–70.PubMedCrossRefGoogle Scholar
  177. 177.
    Custer SK, Gilson TD, Li H, Todd AG, Astroski JW, Lin H, et al. Altered mRNA splicing in SMN-depleted motor neuron-like cells. PLoS One. 2016;11(10):e0163954.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Zhang Z, Pinto AM, Wan L, Wang W, Berg MG, Oliva I, et al. Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. Proc Natl Acad Sci U S A. 2013;110(48):19348–53.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Burgess RW, Nguyen QT, Son YJ, Lichtman JW, Sanes JR. Alternatively spliced isoforms of nerve- and muscle-derived agrin: their roles at the neuromuscular junction. Neuron. 1999;23(1):33–44.PubMedCrossRefGoogle Scholar
  180. 180.
    Wishart TM, Mutsaers CA, Riessland M, Reimer MM, Hunter G, Hannam ML, et al. Dysregulation of ubiquitin homeostasis and beta-catenin signaling promote spinal muscular atrophy. J Clin Invest. 2014;124(4):1821–34.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Mutsaers CA, Lamont DJ, Hunter G, Wishart TM, Gillingwater TH. Label-free proteomics identifies Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers for spinal muscular atrophy. Genome Med. 2013;5(10):95.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Sarvestany AA, Hunter G, Tavendale A, Lamont DJ, Hurtado ML, Graham LC, et al. Label-free quantitative proteomic profiling identifies disruption of ubiquitin homeostasis as a key driver of Schwann cell defects in spinal muscular atrophy. J Proteome Res. 2014;13(11):4546–57.CrossRefGoogle Scholar
  183. 183.
    Fuller HR, Mandefro B, Shirran SL, Gross AR, Kaus AS, Botting CH, et al. Spinal muscular atrophy patient iPSC-derived motor neurons have reduced expression of proteins important in neuronal development. Front Cell Neurosci. 2016;9:506.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Doktor TK, Hua Y, Andersen HS, Broner S, Liu YH, Wieckowska A, et al. RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns. Nucleic Acids Res. 2017;45(1):395–416.PubMedCrossRefGoogle Scholar
  185. 185.
    Jablonka S, Karle K, Sandner B, Andreassi C, von Au K, Sendtner M. Distinct and overlapping alterations in motor and sensory neurons in a mouse model of spinal muscular atrophy. Hum Mol Genet. 2006;15(3):511–8.PubMedCrossRefGoogle Scholar
  186. 186.
    Jablonka S, Schrank B, Kralewski M, Rossoll W, Sendtner M. Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III. Hum Mol Genet. 2000;9(3):341–6.PubMedCrossRefGoogle Scholar
  187. 187.
    Wurth L, Gribling-Burrer AS, Verheggen C, Leichter M, Takeuchi A, Baudrey S, et al. Hypermethylated-capped selenoprotein mRNAs in mammals. Nucleic Acids Res. 2014;42(13):8663–77.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Phillip L. Price
    • 1
    • 2
  • Dmytro Morderer
    • 1
  • Wilfried Rossoll
    • 1
    Email author
  1. 1.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  2. 2.Department of Cell BiologyEmory UniversityAtlantaUSA

Personalised recommendations