80
Views
0
CrossRef citations to date
0
Altmetric
Review

Motor Neuron Biology and Disease: A Current Perspective on Infantile-Onset Spinal Muscular Atrophy

, &
Pages 161-172 | Received 19 Mar 2018, Accepted 22 May 2018, Published online: 06 Jul 2018

References

  • Sugarman EA , NaganN, ZhuHet al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur. J. Hum. Genet.20(1), 27–32 (2012).
  • Hendrickson BC , DonohoeC, AkmaevVRet al. Differences in SMN1 allele frequencies among ethnic groups within North America. J. Med Genet.46(9), 641–644 (2009).
  • Wang CH , LunnMR. Spinal muscular atrophy: advances in research and consensus on care of patients. Curr. Treat. Options Neurol.10(6), 420–428 (2008).
  • Grotto S , CuissetJM, MarretSet al. Type 0 spinal muscular atrophy: further delineation of prenatal and postnatal features in 16 patients. J. Neuromuscul. Dis.3(4), 487–495 (2016).
  • Clermont O , BurletP, LefebvreSet al. SMN gene deletions in adult-onset spinal muscular atrophy. Lancet346(8991–8992), 1712–1713 (1995).
  • Kline RA , KaiferKA, OsmanEYet al. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases. PLoS Genet.13(3), e1006680 (2017).
  • Boyd PJ , TuWY, ShorrockHKet al. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy. PLoS Genet.13(4), e1006744 (2017).
  • Boyer JG , MurrayLM, ScottK, De RepentignyY, RenaudJM, Kothary. Early onset muscle weakness and disruption of muscle proteins in mouse models of spinal muscular atrophy. Skelet. Muscle3(1), 24 (2013).
  • Bowerman M , SwobodaKJ, MichalskiJPet al. Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann. Neurol.72(2), 256–268 (2012).
  • Bowerman M , MichalskiJP, BeauvaisA, MurrayLM, DeRepentignyY, KotharyR. Defects in pancreatic development and glucose metabolism in SMN-depleted mice independent of canonical spinal muscular atrophy neuromuscular pathology. Hum. Mol. Genet.23(13), 3432–3444 (2014).
  • Deguise MO , KotharyR. New insights into SMA pathogenesis: immune dysfunction and neuroinflammation. Ann. Clin. Transl. Neurol.4(7), 522–530 (2017).
  • Somers E , StencelZ, WishartTM, GillingwaterTH, ParsonSH. Density, calibre and ramification of muscle capillaries are altered in a mouse model of severe spinal muscular atrophy. Neuromuscul. Disord.22(5), 435–442 (2012).
  • Hunter G , Aghamaleky SarvestanyA, RocheSL, SymesRC, GillingwaterTH. SMN-dependent intrinsic defects in Schwann cells in mouse models of spinal muscular atrophy. Hum. Mol. Genet.23(9), 2235–2250 (2014).
  • Rindt H , FengZ, MazzasetteC, GlascockJJet al. Astrocytes influence the severity of spinal muscular atrophy. Hum. Mol. Genet.24(14), 4094–4102 (2015).
  • Werdnig G . Zwei frühinfantile hereditäre Fälle von progressiver Muskelatrophie unter dem Bilde der Dystrophie, aber auf neurotischer Grundlage. Arch. Psychiat. Nervenkr.22, 437–480 (1891).
  • Hoffmann J . Ueber chronische spinale Muskelatrophie im Kindesalter, auf familiärer Basis. Deutsch Z Nervenheilk3, 427–470 (1893).
  • Hoffmann J . Weiterer Beitrag zur Lehre von der hereditären progressiven spinalen Muskelatrophie im Kindesalter nebst Bemerkungen über den fortschreitenden Muskelschwund im Allgemeinen. Deutsch Z Nervenheilk10, 292–320 (1897).
  • Hoffmann J . Dritter Beitrag zur Lehre von der hereditären progressiven spinalen Muskelatrophie im Kindesalter. Deutsch Z Nervenheilk18, 217–224 (1900).
  • Lefebvre S , BurglenL, ReboulletSet al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell80(1), 155–165 (1995).
  • Rochette CF , GilbertN, SimardLR. SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum. Genet.108(3), 255–266 (2001).
  • Monani UR , LorsonCL, ParsonsDWet al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum. Mol. Genet.8(7), 1177–1183 (1999).
  • Lorson CL , HahnenE, AndrophyEJ, WirthB. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc. Natl Acad. Sci. USA96(11), 6307–6311 (1999).
  • Kashima T , ManleyJL. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat. Genet.34(4), 460–463 (2003).
  • Cho S , DreyfussG. A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. Genes Dev.24(5), 438–442 (2010).
  • Coovert DD , LeTT, McAndrewPEet al. The survival motor neuron protein in spinal muscular atrophy. Hum. Mol. Genet.6(8), 1205–1214 (1997).
  • Lefebvre S , BurletP, LiuQet al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat. Genet.16(3), 265–269 (1997).
  • McAndrew PE , ParsonsDW, SimardLRet al. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am. J. Hum Genet.60(6), 1411–22 (1997).
  • Feldkotter M , SchwarzerV, WirthR, WienkerTF, WirthB. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am. J. Hum. Genet.70(2), 358–368 (2002).
  • Prior TW , KrainerAR, HuaYet al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am. J. Hum. Genet.85(3), 408–413 (2009).
  • Wu X , WangSH, SunJ, KrainerAR, HuaY, PriorTW. A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. Hum. Mol. Genet.26(14), 2768–2780 (2017).
  • Liu Q , DreyfussG. A novel nuclear structure containing the survival of motor neurons protein. EMBO J.15(14), 3555–3565 (1996).
  • Young PJ , LeTT, thi ManN, BurghesAH, MorrisGE. The relationship between SMN, the spinal muscular atrophy protein, and nuclear coiled bodies in differentiated tissues and cultured cells. Exp. Cell Res.256(2), 365–374 (2000).
  • Liu Q , FischerU, WangF, DreyfussG. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell90(6), 1013–1021 (1997).
  • Fischer U , LiuQ, DreyfussG. The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell90(6), 1023–1029 (1997).
  • Pellizzoni L , KataokaN, CharrouxB, DreyfussG. A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell95(5), 615–624 (1998).
  • Chari A , PakniaE, FischerU. The role of RNP biogenesis in spinal muscular atrophy. Curr. Opin. Cell Biol.21(3), 387–393 (2009).
  • Grimmler M , OtterS, PeterC, MüllerF, ChariA, FischerU. Unrip, a factor implicated in cap-independent translation, associates with the cytosolic SMN complex and influences its intracellular localization. Hum. Mol. Genet.14(20), 3099–3111 (2005).
  • Chari A , GolasMM, KlingenhägerMet al. An assembly chaperone collaborates with the SMN complex to generate spliceosomal SnRNPs. Cell135(3), 497–509 (2008).
  • Narayanan U , OspinaJK, FreyMR, HebertMD, MateraAG. SMN, the spinal muscular atrophy protein, forms a pre-import snRNP complex with snurportin1 and importin beta. Hum. Mol. Genet.11(15), 1785–1795 (2002).
  • Narayanan U , AchselT, LührmannR, MateraAG. Coupled in vitro import of U snRNPs and SMN, the spinal muscular atrophy protein. Mol. Cell16(2), 223–234 (2004).
  • Schrank B , GötzR, GunnersenJMet 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. USA94(18), 9920–9925 (1997).
  • Jablonka S , HoltmannB, MeisterGet al. Gene targeting of Gemin2 in mice reveals a correlation between defects in the biogenesis of U snRNPs and motoneuron cell death. Proc. Natl Acad. Sci. USA99(15), 10126–10131 (2002).
  • Mouillet JF , YanX, OuQet al. DEAD-box protein-103 (DP103, Ddx20) is essential for early embryonic development and modulates ovarian morphology and function. Endocrinology149(5), 2168–2175 (2008).
  • Shpargel KB , PraveenK, RajendraTK, MateraAG. Gemin3 is an essential gene required for larval motor function and pupation in Drosophila. Mol. Biol. Cell20(1), 90–101 (2009).
  • Meier ID , WalkerMP, MateraAG. Gemin4 is an essential gene in mice, and its overexpression in human cells causes relocalization of the SMN complex to the nucleoplasm. Biol. Open7(2), pii: bio032409 (2018).
  • Gates J , LamG, OrtizJA, LossonR, ThummelCS. rigor mortis encodes a novel nuclear receptor interacting protein required for ecdysone signaling during Drosophila larval development. Development131(1), 25–36 (2004).
  • Wan L , BattleDJ, YongJet al. The survival of motor neurons protein determines the capacity for snRNP assembly: biochemical deficiency in spinal muscular atrophy. Mol. Cell. Biol.25(13), 5543–5551 (2005).
  • Zhang Z , LottiF, DittmarKet al. SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell133(4), 585–600 (2008).
  • Kim JK , CaineC, AwanoT, HerbstR, MonaniUR. Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice. Hum. Mol. Genet.26(13), 2377–2385 (2017).
  • Lotti F , ImlachWL, SaievaLet al. An SMN-dependent U12 splicing event essential for motor circuit function. Cell151(2), 440–454 (2012).
  • Zhang Z , PintoAM, WanLet al. Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. Proc. Natl Acad. Sci. USA110(48), 19348–19353 (2013).
  • Workman E , SaievaL, CarrelTLet al. A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice. Hum. Mol. Genet.18(12), 2215–2229 (2009).
  • Gabanella F , ButchbachME, SaievaL, CarissimiC, BurghesAH, PellizzoniL. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS One2(9), e921 (2007).
  • Ruggiu M , McGovernVL, LottiFet al. A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy. Mol. Cell. Biol.32(1), 126–38 (2012).
  • Jodelka FM , EbertAD, DuelliDM, HastingsML. A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2. Hum. Mol. Genet.19(24), 4906–4917 (2010).
  • Comley LH , NijssenJ, Frost-NylenJ, HedlundE. Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology. J. Comp. Neurol.524(7), 1424–1442 (2016).
  • Steiman GS , RorkeLB, BrownMJ. Infantile neuronal degeneration masquerading as Werdnig-Hoffmann disease. Ann. Neurol.8(3), 317–324 (1980).
  • Wishart TM , MutsaersCA, RiesslandMet al. Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy. J. Clin. Invest.124(4), 1821–1834 (2014).
  • Ripolone M , RonchiD, ViolanoRet al. Impaired muscle mitochondrial biogenesis and myogenesis in spinal muscular atrophy. JAMA Neurol.72(6), 666–675 (2015).
  • Sanchez G , DuryAY, MurrayLMet al. A novel function for the survival motoneuron protein as a translational regulator. Hum. Mol. Genet.22(4), 668–684 (2013).
  • Strasswimmer J , LorsonCL, BreidingDEet al. Identification of survival motor neuron as a transcriptional activator-binding protein. Hum. Mol. Genet.8(7), 1219–1226 (1999).
  • Rossoll W , KröningAK, OhndorfUM, SteegbornC, JablonkaS, SendtnerM. 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.11(1), 93–105 (2002).
  • McWhorter ML , MonaniUR, BurghesAH, BeattieCE. Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding. J. Cell Biol.162(5), 919–931 (2003).
  • Kariya S , MauricioR, DaiY, MonaniUR. The neuroprotective factor Wld(s) fails to mitigate distal axonal and neuromuscular junction (NMJ) defects in mouse models of spinal muscular atrophy. Neurosci. Lett.449(3), 246–251 (2009).
  • Murray LM , ComleyLH, ThomsonD, ParkinsonN, TalbotK, GillingwaterTH. Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy. Hum. Mol. Genet.17(7), 949–962 (2008).
  • Ling KK , LinMY, ZinggB, FengZ, KoCP. Synaptic defects in the spinal and neuromuscular circuitry in a mouse model of spinal muscular atrophy. PLoS One5(11), e15457 (2010).
  • Kariya S , ParkGH, Maeno-HikichiYet al. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum. Mol. Genet.17(16), 2552–2569 (2008).
  • Zhang H , XingL, RossollW, WichterleH, SingerRH, BassellGJ. Multiprotein complexes of the survival of motor neuron protein SMN with Gemins traffic to neuronal processes and growth cones of motor neurons. J. Neurosci.26(33), 8622–8632 (2006).
  • Rossoll W , KröningAK, OhndorfUM, SteegbornC, JablonkaS, SendtnerM. 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.11(1), 93–105 (2002).
  • Akten B , KyeMJ, Hao leTet al. Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. Proc. Natl Acad. Sci. USA108(25), 10337–10342 (2011).
  • Tadesse H , Deschênes-FurryJ, BoisvenueS, CôtéJ. KH-type splicing regulatory protein interacts with survival motor neuron protein and is misregulated in spinal muscular atrophy. Hum. Mol. Genet.17(4), 506–524 (2008).
  • Hubers L , Valderrama-CarvajalH, LaframboiseJ, TimbersJ, SanchezG, CôtéJ. HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects. Hum. Mol. Genet.20(3), 553–579 (2011).
  • Mobarak CD , AndersonKD, MorinMet al. The RNA-binding protein HuD is required for GAP-43 mRNA stability, GAP-43 gene expression, and PKC-dependent neurite outgrowth in PC12 cells. Mol. Biol. Cell11(9), 3191–3203 (2000).
  • Aranda-Abreu GE , BeharL, ChungS, FurneauxH, GinzburgI. Embryonic lethal abnormal vision-like RNA-binding proteins regulate neurite outgrowth and tau expression in PC12 cells. J. Neurosci.19(16), 6907–6917 (1999).
  • Deschênes-Furry J , MousaviK, BolognaniFet al. The RNA-binding protein HuD binds acetylcholinesterase mRNA in neurons and regulates its expression after axotomy. J. Neurosci.27(3), 665–675 (2007).
  • Fallini C , Donlin-AspPG, RouanetJP, BassellGJ, RossollW. Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA-binding protein IMP1 facilitates its trafficking into motor neuron axons. J. Neurosci.36(13), 3811–3820 (2016).
  • Hao le T , DuyPQ, AnMet al. HuD and the survival motor neuron protein interact in motoneurons and are essential for motoneuron development, function, and mRNA Regulation. J. Neurosci.37(48), 11559–11571 (2017).
  • Wirth B , TessaroloD, HahnenEet al. Different entities of proximal spinal muscular atrophy within one family. Hum. Genet.100(5–6), 676–680 (1997).
  • Oprea GE , KröberS, McWhorterMLet al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science320(5875), 524–527 (2008).
  • Hosseinibarkooie S , PetersM, Torres-BenitoLet al. The power of human protective modifiers: PLS3 and CORO1C unravel impaired endocytosis in spinal muscular atrophy and rescue SMA phenotype. Am. J. Hum. Genet.99(3), 647–665 (2016).
  • Riessland M , KaczmarekA, SchneiderSet al. Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis. Am. J. Hum. Genet.100(2), 297–315 (2017).
  • Torres-Benito L , NeherMF, CanoR, RuizR, TabaresL. SMN requirement for synaptic vesicle, active zone and microtubule postnatal organization in motor nerve terminals. PLoS One6(10), e26164 (2011).
  • Tejero R , Lopez-ManzanedaM, ArumugamS, TabaresL. Synaptotagmin-2, and -1, linked to neurotransmission impairment and vulnerability in spinal muscular atrophy. Hum. Mol. Genet.25(21), 4703–4716 (2016).
  • Bowerman M , AndersonCL, BeauvaisA, BoylPP, WitkeW, KotharyR. SMN, profilin IIa and plastin 3: a link between the deregulation of actin dynamics and SMA pathogenesis. Mol. Cell. Neurosci.42(1), 66–74 (2009).
  • Hensel N , ClausP. The actin cytoskeleton in SMA and ALS: how does it contribute to motoneuron degeneration?Neuroscientist24(1), 54–72 (2018).
  • Bowerman M , BeauvaisA, AndersonCL, KotharyR. Rho-kinase inactivation prolongs survival of an intermediate SMA mouse model. Hum. Mol. Genet.19(8), 1468–1478 (2010).
  • Bowerman M , MurrayLM, BoyerJG, AndersonCL, KotharyR. Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy. BMC Med.10, 24 (2012).
  • Hamilton G , GillingwaterTH. Spinal muscular atrophy: going beyond the motor neuron. Trends Mol. Med.19(1), 40–50 (2013).
  • Nash LA , BurnsJK, ChardonJW, KotharyR, ParksRJ. Spinal muscular atrophy: more than a disease of motor neurons?Curr. Mol. Med.16(9), 779–792 (2016).
  • Gavrilina TO , McGovernVL, WorkmanEet al. Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum. Mol. Genet.17(8), 1063–1075 (2008).
  • Iyer CC , McGovernVL, MurrayJDet al. Low levels of Survival Motor Neuron protein are sufficient for normal muscle function in the SMNΔ7 mouse model of SMA. Hum. Mol. Genet.24(21), 6160–6173 (2015).
  • Martinez TL , KongL, WangXet al. Survival Motor Neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. J. Neurosci.32(25), 8703–8715 (2012).
  • Monani UR , SendtnerM, CoovertDDet 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.9(3), 333–339 (2000).
  • Hsieh-Li HM , ChangJG, JongYJet al. (2000) A mouse model for spinal muscular atrophy. Nat. Genet.24(1), 66–70 (2007).
  • Singh NK , SinghNN, AndrophyEJ, SinghRN. Splicing of a critical exon of human survival motor neuron is regulated by a unique silencer element located in the last intron. Mol. Cell. Biol.26(4), 1333–1346 (2006).
  • Hua Y , SahashiK, HungGet al. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am. J. Hum. Genet.82(4), 834–848 (2008).
  • Kim JK , MonaniUR. Augmenting the SMN protein to treat infantile spinal muscular atrophy. Neuron97(5), 1001–1003 (2018).
  • Finkel RS , MercuriE, DarrasBTet al. Nusinersen versus Sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med.377(18), 1723–1732 (2017).
  • https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm534611.htm.
  • Foust KD , NurreE, MontgomeryCL, HernandezA, ChanCM, KasparBK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol.27(1), 59–65 (2009).
  • Bucher T , ColleMA, WakelingEet al. scAAV9 intracisternal delivery results in efficient gene transfer to the central nervous system of a feline model of motor neuron disease. Hum. Gene Ther.24(7), 670–82 (2013).
  • Foust KD , WangX, McGovernVLet al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat. Biotech.28(3), 271–274 (2010).
  • Duque SI , ArnoldWD, OdermattPet al. A large animal model of spinal muscular atrophy and correction of phenotype. Ann. Neurol.77(3), 399–414 (2015).
  • Mendell JR , Al-ZaidyS, ShellRet al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med.377(18), 1713–1722 (2017).
  • Bordet T , BernaP, AbitbolJL, PrussRM. Olesoxime (TRO19622): a novel mitochondrial-targeted neuroprotective compound. Pharmaceuticals (Basel).3(2), 345–368 (2010).
  • Bertini E , DessaudE, MercuriEet al. Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled Phase 2 trial. Lancet Neurol.16(7), 513–522 (2017).
  • Andrews JA , MillerTM, VijayakumarVet al. CK-2127107 amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve57(5), 729–734 (2017).
  • Andrews JA , CudkowiczME, HardimanOet al. VITALITY-ALS, a Phase III trial of tirasemtiv, a selective fast skeletal muscle troponin activator, as a potential treatment for patients with amyotrophic lateral sclerosis: study design and baseline characteristics. Amyotroph. Lateral Scler. Frontotemporal Degener.19(3–4), 259–266 (2018).
  • Lutz CM , KariyaS, PatruniSet al. Post-symptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J. Clin. Invest.121(8), 3029–3041 (2011).
  • Kariya S , ObisT, GaroneCet al. Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation. J. Clin. Invest.124(2), 785–800 (2014).
  • Mercuri E , DarrasBT, ChiribogaCAet al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N. Engl. J. Med.378(7), 625–635 (2018).
  • van der Ploeg AT . The dilemma of two innovative therapies for spinal muscular atrophy. N. Engl. J. Med.377(18), 1786–1787 (2017).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.