Neurodegeneration in spinal muscular atrophy: From disease phenotype and animal models to therapeutic strategies and beyond

Future Neurology

Volumn 9, Issue 1, 2014, Pages 49-65

  Monani, Umrao R ^a   De Vivo, Darryl C ^a  

^a NewYork Presbyterian Hospital   (United States)

Author keywords

animal models; motor neuron; neurodegeneration; spinal muscular atrophy; survival motor neuron

Indexed keywords

4 AMINOPYRIDINE; 4 PHENYLBUTYRIC ACID; ANTISENSE OLIGONUCLEOTIDE; GABAPENTIN; HISTONE DEACETYLASE INHIBITOR; HYDROXYUREA; RILUZOLE; SALBUTAMOL; SURVIVAL MOTOR NEURON PROTEIN; VALPROIC ACID;

CLINICAL FEATURE; DISEASE CLASSIFICATION; DISEASE COURSE; DISEASE MODEL; GENE; HETEROZYGOTE; HUMAN; INCIDENCE; MOLECULAR GENETICS; NERVE DEGENERATION; NONHUMAN; PATHOLOGY; PATIENT CARE; PRIORITY JOURNAL; REVIEW; SMN1 GENE; SMN2 GENE; SPINAL MUSCULAR ATROPHY; TREATMENT RESPONSE;

EID: 84890901142     PISSN: 14796708     EISSN: 17486971     Source Type: Journal    
DOI: 10.2217/fnl.13.58     Document Type: Review

References (109)

1. 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).
2. Hoffmann J. Ueber chronische spinale Muskelatrophie im Kindesalter, auf familiärer Basis. Deutsch. Z. Nervenheilk. 3, 427-470 (1893).
3. Hoffmann J. Weiterer Beitrag zur Lehre von der hereditären progressiven spinalen Muskelatrophie im Kindesalter nebst Bemerkungen über den fortschreitenden Muskelschwund im Allgemeinen. Deutsch. Z. Nervenheilk. 10, 292-320 (1897).
4. Hoffmann J. Dritter Beitrag zur Lehre von der hereditären progressiven spinalen Muskelatrophie im Kindesalter. Deutsch. Z. Nervenheilk. 18, 217-224 (1900).
5. Kugelberg E, Welander L. Heredofamilial juvenile muscular atrophy simulating muscular dystrophy. AMA Arch. Neurol. Psychiatry 75, 500-509 (1956).
6. Thompson J, Bruce A. Progressive muscular atrophy in a child with a spinal lesion. Edinb. Hosp. Rep. 1, 372 (1893).
7. Dubowitz V. Infantile muscular atrophy. A prospective study with particular reference to a slowly progressive variety. Brain 87, 707-718 (1964).
8. Clermont O, Burlet P, Lefebvre S et al. SMN gene deletions in adult-onset spinal muscular atrophy. Lancet 346(8991-8992), 1712-1713 (1995).
9. Brahe C, Servidei S, Zappata S, Ricci E, Tonali P, Neri G. Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy. Lancet 346(8977), 741-742 (1995).
10. Kang PB, Krishnamoorthy KS, Jones RM, Shapiro FD, Darras BT. Atypical presentations of spinal muscular atrophy type III (Kugelberg-Welander disease). Neuromuscul. Disord. 16(8), 492-494 (2006).
11. Hausmanowa-Petrusewicz I. Electrophysiological findings in childhood spinal muscular atrophies. Rev. Neurol. (Paris) 144(11), 716-720 (1988).
12. Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve 25(3), 445-447 (2002).
13. Hausmanowa-Petrusewicz I, Karwa?ska A. Electromyographic findings in different forms of infantile and juvenile proximal spinal muscular atrophy. Muscle Nerve 9(1), 37-46 (1986).
14. Crawford TO, Pardo CA. The neurobiology of childhood spinal muscular atrophy. Neurobiol. Dis. 3(2), 97-110 (1996).
15. Simic G, Mladinov M, Seso Simic D et al. Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy. Acta Neuropathol. 115(3), 313-326 (2008).
16. Dubowitz V. Muscle Disorders in Childhood (2nd Edition). Saunders, PA, USA (1995).
17. Nadeau A, D'Anjou G, Debray G, Robitaille Y, Simard LR, Vanasse M. A newborn with spinal muscular atrophy type 0 presenting with a clinicopathological picture suggestive of myotubular myopathy. J. Child Neurol. 22(11), 1301-1304 (2007).
18. Kariya S, Park GH, Maeno-Hikichi Y et 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).
19. Gilliam TC, Brzustowicz LM, Castilla LH et al. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature 345(6278), 823-825 (1990).
20. Brzustowicz LM, Lehner T, Castilla LH et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 344(6266), 540-541 (1990).
21. Lefebvre S, Burglen L, Reboullet S et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80(1), 155-165 (1995).
22. Monani UR, Lorson CL, Parsons DW et 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).
23. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc. Natl Acad. Sci. USA 96(11), 6307-6311 (1999).
24. Kashima T, Manley JL. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat. Genet. 34(4), 460-463 (2003).
25. Coovert DD, Le TT, McAndrew PE et al. The survival motor neuron protein in spinal muscular atrophy. Hum. Mol. Genet. 6(8), 1205-1214 (1997).
26. Lefebvre S, Burlet P, Liu Q et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat. Genet. 16(3), 265-269 (1997).
27. McAndrew PE, Parsons DW, Simard LR et 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), 1411-1422 (1997).
28. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. 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).
29. Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. EMBO J. 15(14), 3555-3565 (1996).
30. Battle DJ, Kasim M, Yong J et al. The SMN complex: an assembly machine for RNPs. Cold Spring Harb. Symp. Quant. Biol. 71, 313-320 (2006).
31. Carrel TL, McWhorter ML, Workman E et al. Survival motor neuron function in motor axons is independent of functions required for small nuclear ribonucleoprotein biogenesis. J. Neurosci. 26(43), 11014-11022 (2006).
32. 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. 1(6), 624-631 (2012).
33. Lotti F, Imlach WL, Saieva L et al. An SMN-dependent U12 splicing event essential for motor circuit function. Cell 151(2), 440-454 (2012).
34. Burghes AH, Beattie CE. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat. Rev. Neurosci. 10(8), 597-609 (2009).
35. 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. 26(33), 8622-8632 (2006).
36. Rossoll W, Kröning 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. 11(1), 93-105 (2002).
37. Akten B, Kye MJ, Hao le T et al. Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. Proc. Natl Acad. Sci. USA 108(25), 10337-10342 (2011).
38. Tadesse H, Deschênes-Furry J, Boisvenue S, Côté J. 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).
39. Hubers L, Valderrama-Carvajal H, Laframboise J, Timbers J, Sanchez G, Côté J. HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects. Hum. Mol. Genet. 20(3), 553-579 (2011).
40. Oprea GE, Krober S, McWhorter ML et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 320(5875), 524-527 (2008).
41. Bowerman M, Beauvais A, Anderson CL, Kothary R. Rho-kinas inactivation prolongs survival of an intermediate SMA mouse model. Hum. Mol. Genet. 19(8), 1468-1478 (2010).
42. Nölle A, Zeug A, van Bergeijk J et al. The spinal muscular atrophy disease protein SMN is linked to the Rho-kinase pathway via profiling. Hum. Mol. Genet. 20(24), 4865-4878 (2011).
43. Schrank B, Gotz, R, Gunnerson JM 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. USA 94(18), 9920-9925 (1997).
44. Schmid A, DiDonato CJ. Animal models of spinal muscular atrophy. J. Child Neurol. 22, 1004-1012 (2007).
45. Hsieh-Li HM, Chang JG, Jong YJ et al. A mouse model for spinal muscular atrophy. Nat. Genet. 24(1), 66-70 (2000).
46. Monani UR, Sendtner M, Coovert DD 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. 9(3), 333-339 (2000).
47. Bernal S, Also-Rasso E, Alias L et al. Synaptic defects in type 1 spinal muscular atrophy in human development. J. Pathol. 229(1), 49-61 (2013).
48. Park GH, Maeno-Hikichi Y, Awano T, Landmesser LT, Monani UR. Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene. J. Neurosci. 30(36), 12005-12019 (2010).
49. Ling KK, Lin MY, Zingg B, Feng Z, Ko CP. Synaptic defects in the spinal and neuromuscular circuitry in a mouse model of spinal muscular atrophy. PLoS ONE 5(11), e15457 (2010).
50. Mentis GZ, Blivis D, Liu W et al. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron 69(3), 453-467 (2011).
51. Heier CR, Satta R, Lutz C, DiDonato CJ. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum. Mol. Genet. 19(20), 3906-3918 (2010).
52. Wishart TM, Huang JP, Murray LM et al. SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy. Hum. Mol. Genet. 19(22), 4216-4228 (2010).
53. Mutsaers CA, Wishart TM, Lamont DJ et al. Reversible molecular pathology of skeletal muscle in spinal muscular atrophy. Hum. Mol. Genet. 20, 4334-4344 (2011).
54. Araujo Ade Q, Araujo M, Swoboda KJ. Vascular perfusion abnormalities in infants with spinal muscular atrophy. J. Pediatr. 155(2), 292-294 (2009).
55. Workman E, Saieva L, Carrel TL et al. A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice. Hum. Mol. Genet. 18(12), 2215-2229 (2009).
56. Gavrilina TO, McGovern VL, Workman E 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. 17(8), 1063-1075 (2008).
57. Martinez TL, Kong L, Wang X et al. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. J. Neurosci. 32(25), 8703-8715 (2012).
58. Gogliotti RG, Quinlan KA, Barlow CB et al. 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. 32(11), 3818-3829 (2012).
59. Lee AJ, Awano T, Park GH, Monani UR. Limited phenotypic effects of selectively augmenting the SMN protein in the neurons of a mouse model of severe spinal muscular atrophy. PLoS ONE 7(9), e46353 (2012).
60. Le TT, McGovern VL, Alwine IE et al. Temporal requirement for high SMN expression in SMA mice. Hum. Mol. Genet. 20, 3578-3591 (2011).
61. Lutz CM, Kariya S, Patruni S et 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).
62. Avila AM, Burnett BG, Taye AA et al. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J. Clin. Invest. 117(3), 659-671 (2007).
63. Echaniz-Laguna A, Bousiges O, Loeffler JP et al. Histone deacetylase inhibitors: therapeutic agents and research tools for deciphering motor neuron diseases. Curr. Med. Chem. 15(13), 1263-1273 (2008).
64. Sumner CJ, Huynh TN, Markowitz JA et al. Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann. Neurol. 54(5), 647-654 (2003).
65. Chang JG, Hsieh-Li HM, Jong YJ et al. Treatment of spinal muscular atrophy by sodium butyrate. Proc. Natl Acad. Sci. USA 98(17), 9808-9813 (2001).
66. Grzeschik SM, Ganta M, Prior TW, Heavlin WD, Wang CH. Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells. Ann. Neurol. 58(2), 194-202 (2005).
67. Riessland M, Ackermann B, Förster A et al. SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy. Hum. Mol. Genet. 19(8), 1492-1506 (2010).
68. Brahe C, Vitali T, Tiziano FD et al. Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. Eur. J. Hum. Genet. 13(2), 256-259 (2005).
69. Tsai LK, Tsai MS, Ting CH, Li H. Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice. J. Mol. Med. 86(11), 1243-1254 (2008).
70. Chen TH, Chang JG, Yang YH et al. Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy. Neurology 75(24), 2190-2197 (2010).
71. Mercuri E, Bertini E, Messina S et al. Pilot trial of phenylbutyrate in spinal muscular atrophy. Neuromusc. Disord. 14(2), 130-135 (2004).
72. Swoboda KJ, Scott CB, Reyna SP et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS ONE 4(5), e5268 (2009).
73. Mercuri E, Bertini E, Messina S et al. Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy. Neurology 68(1), 51-55 (2007).
74. Pane M, Staccioli S, Messina S et al. Daily salbutamol in young patients with SMA type II. Neuromusc. Disord. 18(7), 536-540 (2008).
75. Russman BS, Iannaccone ST, Samaha FJ. A Phase 1 trial of riluzole in spinal muscular atrophy. Arch. Neurol. 60(11), 1601-1603 (2003).
76. Miller RG, Moore DH, Dronsky V et al.; SMA Study Group. A placebo-controlled trial of gabapentin in spinal muscular atrophy. J. Neurol. Sci. 191(1-2), 127-131 (2001).
77. Merlini L, Solari A, Vita G et al. Role of gabapentin in spinal muscular atrophy: results of a multicenter, randomized Italian study. J. Child Neurol. 18(8), 537-541 (2003).
78. Oskoui M, Levy G, Garland CJ et al. The changing natural history of spinal muscular atrophy type 1. Neurology 69(20), 1931-1936 (2007).
79. Montes J, Dunaway S, Montgomery MJ et al. Fatigue leads to gait changes in spinal muscular atrophy. Muscle Nerve 43(4), 485-488 (2011).
80. Montes J, McIsaac TL, Dunaway S et al. Falls and spinal muscular atrophy: exploring cause and prevention. Muscle Nerve 47(1) 118-123 (2013).
81. Sproule DM, Montes J, Montgomery M et al. Increased fat mass and high incidence of overweight despite low body mass index in patients with spinal muscular atrophy. Neuromusc. Disord. 19(6), 391-396 (2009).
82. Sproule DM, Montes J, Dunaway S et al. Adiposity is increased among high-functioning, non-ambulatory patients with spinal muscular atrophy. Neuromusc. Disord. 20(7), 448-452 (2010).
83. Wang CH, Finkel RS, Bertini ES et al.; Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J. Child Neurol. 22(8), 1027-1049 (2007).
84. Andreassi C, Jarecki J, Zhou J et al. Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Hum. Mol. Genet. 10(24), 2841-2849 (2001).
85. Lunn MR, Root DE, Martino AM et al. Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism. Chem. Biol. 11(11), 1489-1493 (2004).
86. Garbes L, Riessland M, Hölker I et al. LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate. Hum. Mol. Genet. 18(19), 3645-3658 (2009).
87. Butchbach ME, Singh J, Thorsteinsdóttir M et al. Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy. Hum. Mol. Genet. 19(3), 154-467 (2010).
88. Naryshkin N, Narasimhan J, Dakka A et al. Small molecule compounds correct alternative splicing of the SMN2 gene and restore SMN protein expression and function. Neuromusc. Dis. 22(9-10), 848 (2012).
89. Hua Y, Krainer AR. Antisense-mediated exon inclusion. Methods Mol. Biol. 867, 307-323 (2012).
90. Singh NK, Singh NN, Androphy EJ, Singh RN. 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).
91. Hua Y, Sahashi K, Rigo F et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478(7367), 123-126 (2011).
92. Porensky PN, Mitrpant C, McGovern et al. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum. Mol. Genet. 21(7), 1625-1638 (2012).
93. Mattis VB, Ebert AD, Fosso MY, Chang CW, Lorson CL. Delivery of a read-through inducing compound, TC007, lessens the severity of a spinal muscular atrophy animal model. Hum. Mol. Genet. 18(20), 3906-3913 (2009).
94. Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR. 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).
95. Bowerman M, Murray LM, Boyer JG, Anderson CL, Kothary R. Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy. BMC Med. 10, 24 (2012).
96. Foust KD, Wang X, McGovern VL et 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).
97. Sunyach C, Michaud M, Arnoux T et al. Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model. Neuropharmacology 62(7), 2346-2352 (2012).
98. Valori CF, Ning K, Wyles M et al. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci. Transl. Med. 2(35), 35ra42 (2010).
99. Dominguez E, Marais T, Chatauret N et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum. Mol. Genet. 20(4), 681-693 (2011).
100. Duque S, Joussemet B, Riviere C et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. 17(7), 1187-1196 (2009).
101. Gowing G, Svendsen CN. Stem cell transplantation for motor neuron disease: current approaches and future perspectives. Neurotherapeutics 8(4), 591-606 (2011).
102. Corti S, Nizzardo M, Nardini M et al. Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy. J. Clin. Invest. 118(10), 3316-3330 (2008).
103. Kariya S, Re D, Jacquier A et al. Mutant superoxide dismutase 1 (SOD1), a cause of amyotrophic lateral sclerosis, disrupts the recruitment of SMN, the spinal muscular atrophy protein to nuclear Cajal bodies. Hum. Mol. Genet. 21(15), 3421-3434 (2012).
104. Groen EJ, Fumoto K, Blokhuis AM et al. ALS-associated mutations in FUS disrupt the axonal distribution and function of SMN. Hum. Mol. Genet. 22(18), 3690-3704 (2013).
105. Tsuiji H, Iguchi Y, Furuya A et al. Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol. Med. 5(2), 221-234 (2013).
106. Yamazaki T, Chen S, Yu Y et al. FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep. 2(4), 799-806 (2012).
107. Monani UR. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron 48(6), 885-896 (2005).
108. An Open-label Safety, Tolerability and Dose-range Finding Study of Multiple Doses of ISIS SMNRx in Patient With Spinal Muscular Atrophy (SMNRx -CS2). http://clinicaltrials.gov/show/NCT01703988
109. A Study to Assess the Safety and Pharmacokinetics of ISIS SMNRx in Infants With Spinal Muscular Atrophy. http://clinicaltrials.gov/show/NCT01839656