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Acta Neuropathologica Communications

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Open Access 01-12-2015 | Research

Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn ^2b/- mouse model of spinal muscular atrophy

Authors: Lyndsay M. Murray, Ariane Beauvais, Sabrina Gibeault, Natalie L. Courtney, Rashmi Kothary

Published in: Acta Neuropathologica Communications | Issue 1/2015

Abstract

Introduction

The term motor neuron disease encompasses a spectrum of disorders in which motor neurons are the lost. Importantly, while some motor neurons are lost early in disease and others remain intact at disease end-stage. This creates a valuable experimental paradigm to investigate the factors that regulate motor neuron vulnerability. Spinal muscular atrophy is a childhood motor neuron disease caused by mutations or deletions in the SMN1 gene. Here, we have performed transcriptional analysis on differentially vulnerable motor neurons from an intermediate mouse model of Spinal muscular atrophy at a presymptomatic time point.

Results

We have characterised two differentially vulnerable populations, differing in the level neuromuscular junction loss. Transcriptional analysis on motor neuron cell bodies revealed that reduced Smn levels correlate with a reduction of transcripts associated with the ribosome, rRNA binding, ubiquitination and oxidative phosphorylation. Furthermore, P53 pathway activation precedes neuromuscular junction loss, suggesting that denervation may be a consequence, rather than a cause of motor neuron death in Spinal muscular atrophy. Finally, increased vulnerability correlates with a decrease in the positive regulation of DNA repair.

Conclusions

This study identifies pathways related to the function of Smn and associated with differential motor unit vulnerability, thus presenting a number of exciting targets for future therapeutic development.

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Andrus BM, Blizinsky K, Vedell PT, Dennis K, Shukla PK, Schaffer DJ, Radulovic J, Churchill GA, Redei EE (2012) Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models. Mol Psychiatry 17:49–61. doi:10.1038/mp.2010.119 PubMedCentralCrossRefPubMed

Ascenzi P, Gustincich S, Marino M (2014) Mammalian nerve globins in search of functions. IUBMB Life 66:268–276. doi:10.1002/iub.1267 CrossRefPubMed

Baumer D, Lee S, Nicholson G, Davies JL, Parkinson NJ, Murray LM, Gillingwater TH, Ansorge O, Davies KE, Talbot K (2009) Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy. PLoS Genet 5, e1000773. doi:10.1371/journal.pgen.1000773 PubMedCentralCrossRefPubMed

Bosch-Marce M, Wee CD, Martinez TL, Lipkes CE, Choe DW, Kong L, Van Meerbeke JP, Musaro A, Sumner CJ (2011) Increased IGF-1 in muscle modulates the phenotype of severe SMA mice. Hum Mol Genet 20:1844–1853. doi:10.1093/hmg/ddr067 PubMedCentralCrossRefPubMed

Bowerman M. MLM, Beauvais A., Pinheiro B., Kothary R. (2011) A critical Smn threshold in mice dictates onset of an intermediate Spinal Muscular Atrophy phenotype associated with a distinct neuromuscular junction pathology. Neuromuscul Disord. In Press

Brockington A, Ning K, Heath PR, Wood E, Kirby J, Fusi N, Lawrence N, Wharton SB, Ince PG, Shaw PJ (2013) Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity. Acta Neuropathol 125:95–109. doi:10.1007/s00401-012-1058-5 PubMedCentralCrossRefPubMed

Butterfield RJ, Stevenson TJ, Xing L, Newcomb TM, Nelson B, Zeng W, Li X, Lu HM, Lu H, Farwell Gonzalez KD, Wei JP, Chao EC, Prior TW, Snyder PJ, Bonkowsky JL, Swoboda KJ (2014) Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis. Neurology 82:1322–1330. doi:10.1212/WNL.0000000000000305 PubMedCentralCrossRefPubMed

Coady TH, Lorson CL (2011) SMN in spinal muscular atrophy and snRNP biogenesis. Wiley interdisciplinary reviews RNA 2:546–564. doi:10.1002/wrna.76 CrossRefPubMed

Corti S, Locatelli F, Papadimitriou D, Del Bo R, Nizzardo M, Nardini M, Donadoni C, Salani S, Fortunato F, Strazzer S, Bresolin N, Comi GP (2007) Neural stem cells LewisX+ CXCR4+ modify disease progression in an amyotrophic lateral sclerosis model. Brain j neurol 130:1289–1305. doi:10.1093/brain/awm043 CrossRef

10.

Dachs E, Hereu M, Piedrafita L, Casanovas A, Caldero J, Esquerda JE (2011) Defective neuromuscular junction organization and postnatal myogenesis in mice with severe spinal muscular atrophy. J Neuropathol Exp Neurol 70:444–461. doi:10.1097/NEN.0b013e31821cbd8b CrossRefPubMed

11.

Dale JM, Shen H, Barry DM, Garcia VB, Rose FF Jr, Lorson CL, Garcia ML (2011) The spinal muscular atrophy mouse model, SMADelta7, displays altered axonal transport without global neurofilament alterations. Acta Neuropathol 122:331–341. doi:10.1007/s00401-011-0848-5 PubMedCentralCrossRefPubMed

12.

de Planell-Saguer M, Schroeder DG, Rodicio MC, Cox GA, Mourelatos Z (2009) Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery. Hum Mol Genet 18:2115–2126. doi:10.1093/hmg/ddp134 PubMedCentralCrossRefPubMed

13.

Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4:P3CrossRefPubMed

14.

Engel AG, Shen XM, Selcen D, Sine SM (2015) Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 14:420–434. doi:10.1016/S1474-4422(14)70201-7 CrossRefPubMed

15.

Fallini C, Bassell GJ, Rossoll W (2012) Spinal muscular atrophy: the role of SMN in axonal mRNA regulation. Brain Res 1462:81–92. doi:10.1016/j.brainres.2012.01.044 PubMedCentralCrossRefPubMed

16.

Filezac de L'Etang A, Maharjan N, Cordeiro Brana M, Ruegsegger C, Rehmann R, Goswami A, Roos A, Troost D, Schneider BL, Weis J, Saxena S (2015) Marinesco-Sjogren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS. Nat Neurosci 18:227–238. doi:10.1038/nn.3903 CrossRefPubMed

17.

Fritzsch B (1993) Fast axonal diffusion of 3000 molecular weight dextran amines. J Neurosci Methods 50:95–103CrossRefPubMed

18.

Groen EJ, Fumoto K, Blokhuis AM, Engelen-Lee J, Zhou Y, van den Heuvel DM, Koppers M, van Diggelen F, van Heest J, Demmers JA, Kirby J, Shaw PJ, Aronica E, Spliet WG, Veldink JH, van den Berg LH, Pasterkamp RJ (2013) ALS-associated mutations in FUS disrupt the axonal distribution and function of SMN. Hum Mol Genet 22:3690–3704. doi:10.1093/hmg/ddt222 CrossRefPubMed

19.

Guenther UP, Handoko L, Laggerbauer B, Jablonka S, Chari A, Alzheimer M, Ohmer J, Plottner O, Gehring N, Sickmann A, von Au K, Schuelke M, Fischer U (2009) IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1). Hum Mol Genet 18:1288–1300. doi:10.1093/hmg/ddp028 CrossRefPubMed

20.

Hammond SM, Gogliotti RG, Rao V, Beauvais A, Kothary R, DiDonato CJ (2010) Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late. PLoS One 5, e15887. doi:10.1371/journal.pone.0015887 PubMedCentralCrossRefPubMed

21.

He Y, Hua Y, Liu W, Hu H, Keep RF, Xi G (2009) Effects of cerebral ischemia on neuronal hemoglobin. official journal of the International Society of Cerebral Blood F. 29:596–605. doi:10.1038/jcbfm.2008.145 CrossRef

22.

Hedlund E, Karlsson M, Osborn T, Ludwig W, Isacson O (2010) Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection. Brain j neurol 133:2313–2330. doi:10.1093/brain/awq167 CrossRef

23.

Hsieh-Li HM, Chang JG, Jong YJ, Wu MH, Wang NM, Tsai CH, Li H (2000) A mouse model for spinal muscular atrophy. Nat Genet 24:66–70. doi:10.1038/71709 CrossRefPubMed

24.

Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF, Krainer AR (2011) Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478:123–126. doi:10.1038/nature10485 PubMedCentralCrossRefPubMed

25.

Jablonka S, Beck M, Lechner BD, Mayer C, Sendtner M (2007) Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy. J Cell Biol 179:139–149. doi:10.1083/jcb.200703187 PubMedCentralCrossRefPubMed

26.

Kanning KC, Kaplan A, Henderson CE (2010) Motor neuron diversity in development and disease. Annu Rev Neurosci 33:409–440. doi:10.1146/annurev.neuro.051508.135722 CrossRefPubMed

27.

Kaplan A, Spiller KJ, Towne C, Kanning KC, Choe GT, Geber A, Akay T, Aebischer P, Henderson CE (2014) Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration. Neuron 81:333–348. doi:10.1016/j.neuron.2013.12.009 CrossRefPubMed

28.

Kariya S, Park GH, Maeno-Hikichi Y, Leykekhman O, Lutz C, Arkovitz MS, Landmesser LT, Monani UR (2008) Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum Mol Genet 17:2552–2569. doi:10.1093/hmg/ddn156 PubMedCentralCrossRefPubMed

29.

Kong L, Wang X, Choe DW, Polley M, Burnett BG, Bosch-Marce M, Griffin JW, Rich MM, Sumner CJ (2009) Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice. J Neurosci 29:842–851. doi:10.1523/JNEUROSCI.4434-08.2009 PubMedCentralCrossRefPubMed

30.

Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208. doi:10.1126/science.1166066 CrossRefPubMed

31.

Le TT, Pham LT, Butchbach ME, Zhang HL, Monani UR, Coovert DD, Gavrilina TO, Xing L, Bassell GJ, Burghes AH (2005) 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 14:845–857. doi:10.1093/hmg/ddi078 CrossRefPubMed

32.

Lefebvre S, Burlet P, Viollet L, Bertrandy S, Huber C, Belser C, Munnich A (2002) A novel association of the SMN protein with two major non-ribosomal nucleolar proteins and its implication in spinal muscular atrophy. Hum Mol Genet 11:1017–1027CrossRefPubMed

33.

Ling KK, Gibbs RM, Feng Z, Ko CP (2012) Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy. Hum Mol Genet 21:185–195. doi:10.1093/hmg/ddr453 PubMedCentralCrossRefPubMed

34.

Ling KK, Lin MY, Zingg B, Feng Z, Ko CP (2010) Synaptic defects in the spinal and neuromuscular circuitry in a mouse model of spinal muscular atrophy. PLoS One 5, e15457. doi:10.1371/journal.pone.0015457 PubMedCentralCrossRefPubMed

35.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408. doi:10.1006/meth.2001.1262 CrossRefPubMed

36.

Lotti F, Imlach WL, Saieva L, Beck ES, le Hao T, Li DK, Jiao W, Mentis GZ, Beattie CE, McCabe BD, Pellizzoni L (2012) An SMN-dependent U12 splicing event essential for motor circuit function. Cell 151:440–454. doi:10.1016/j.cell.2012.09.012 PubMedCentralCrossRefPubMed

37.

Martinez-Hernandez R, Bernal S, Also-Rallo E, Alias L, Barcelo MJ, Hereu M, Esquerda JE, Tizzano EF (2013) Synaptic defects in type I spinal muscular atrophy in human development. J Pathol 229:49–61. doi:10.1002/path.4080 CrossRefPubMed

38.

Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C, Le TT, Jablonka S, Schrank B, Rossoll W, Prior TW, Morris GE, Burghes AH (2000) 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 9:333–339.CrossRefPubMed

39.

Murray LM, Beauvais A, Bhanot K, Kothary R (2013) Defects in neuromuscular junction remodelling in the Smn(2B/-) mouse model of spinal muscular atrophy. Neurobiol Dis 49:57–67. doi:10.1016/j.nbd.2012.08.019 CrossRefPubMed

40.

Murray LM, Comley LH, Thomson D, Parkinson N, Talbot K, Gillingwater TH (2008) 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 17:949–962. doi:10.1093/hmg/ddm367 CrossRefPubMed

41.

Ohyagi Y, Yamada T, Goto I (1994) Hemoglobin as a novel protein developmentally regulated in neurons. Brain Res 635:323–327CrossRefPubMed

42.

Orre M, Kamphuis W, Osborn LM, Melief J, Kooijman L, Huitinga I, Klooster J, Bossers K, Hol EM (2014) Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol Aging 35:1–14. doi:10.1016/j.neurobiolaging.2013.07.008 CrossRefPubMed

43.

Richter F, Meurers BH, Zhu C, Medvedeva VP, Chesselet MF (2009) Neurons express hemoglobin alpha- and beta-chains in rat and human brains. J Comp Neurol 515:538–547. doi:10.1002/cne.22062 PubMedCentralCrossRefPubMed

44.

Ruiz R, Casanas JJ, Torres-Benito L, Cano R, Tabares L (2010) Altered intracellular Ca2+ homeostasis in nerve terminals of severe spinal muscular atrophy mice. J Neurosci 30:849–857. doi:10.1523/JNEUROSCI.4496-09.2010 CrossRefPubMed

45.

Sanchez G, Dury AY, Murray LM, Biondi O, Tadesse H, El Fatimy R, Kothary R, Charbonnier F, Khandjian EW, Cote J (2013) A novel function for the survival motoneuron protein as a translational regulator. Hum Mol Genet 22:668–684. doi:10.1093/hmg/dds474 CrossRefPubMed

46.

Schelshorn DW, Schneider A, Kuschinsky W, Weber D, Kruger C, Dittgen T, Burgers HF, Sabouri F, Gassler N, Bach A, Maurer MH (2009) Expression of hemoglobin in rodent neurons. J cereb blood flow metab : official journal of the International Society of Cerebral Blood Flow and Metabolism 29:585–595. doi:10.1038/jcbfm.2008.152 CrossRef

47.

Shephard F, Greville-Heygate O, Marsh O, Anderson S, Chakrabarti L (2014) A mitochondrial location for haemoglobins--dynamic distribution in ageing and Parkinson's disease. Mitochondrion 14:64–72. doi:10.1016/j.mito.2013.12.001 PubMedCentralCrossRefPubMed

48.

Sleigh JN, Gillingwater TH, Talbot K (2011) The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy. Dis Model Mech 4:457–467. doi:10.1242/dmm.007245 PubMedCentralCrossRefPubMed

49.

Thomson SR, Nahon JE, Mutsaers CA, Thomson D, Hamilton G, Parson SH, Gillingwater TH (2012) Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy. PLoS One 7, e52605. doi:10.1371/journal.pone.0052605 PubMedCentralCrossRefPubMed

50.

Tsai LK, Chen CL, Ting CH, Lin-Chao S, Hwu WL, Dodge JC, Passini MA, Cheng SH (2014) Systemic administration of a recombinant AAV1 vector encoding IGF-1 improves disease manifestations in SMA mice. Mol ther: the journal of the American Society of Gene Therapy 22:1450–1459. doi:10.1038/mt.2014.84 CrossRef

51.

Tsai LK, Chen YC, Cheng WC, Ting CH, Dodge JC, Hwu WL, Cheng SH, Passini MA (2012) IGF-1 delivery to CNS attenuates motor neuron cell death but does not improve motor function in type III SMA mice. Neurobiol Dis 45:272–279. doi:10.1016/j.nbd.2011.06.021 CrossRefPubMed

52.

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211. doi:10.1126/science.1165942 PubMedCentralCrossRefPubMed

53.

Wadman RI, Vrancken AF, van den Berg LH, van der Pol WL (2012) Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3. Neurology 79:2050–2055. doi:10.1212/WNL.0b013e3182749eca CrossRefPubMed

54.

Wehner KA, Ayala L, Kim Y, Young PJ, Hosler BA, Lorson CL, Baserga SJ, Francis JW (2002) Survival motor neuron protein in the nucleolus of mammalian neurons. Brain Res 945:160–173CrossRefPubMed

55.

Wishart TM, Mutsaers CA, Riessland M, Reimer MM, Hunter G, Hannam ML, Eaton SL, Fuller HR, Roche SL, Somers E, Morse R, Young PJ, Lamont DJ, Hammerschmidt M, Joshi A, Hohenstein P, Morris GE, Parson SH, Skehel PA, Becker T, Robinson IM, Becker CG, Wirth B, Gillingwater TH (2014) Dysregulation of ubiquitin homeostasis and beta-catenin signaling promote spinal muscular atrophy. J Clin Invest 124:1821–1834. doi:10.1172/JCI71318 PubMedCentralCrossRefPubMed

56.

Wootz H, Fitzsimons-Kantamneni E, Larhammar M, Rotterman TM, Enjin A, Patra K, Andre E, Van Zundert B, Kullander K, Alvarez FJ (2013) Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model. J Comp Neurol 521:1449–1469. doi:10.1002/cne.23266 PubMedCentralCrossRef

57.

Workman E, Kolb SJ, Battle DJ (2012) Spliceosomal small nuclear ribonucleoprotein biogenesis defects and motor neuron selectivity in spinal muscular atrophy. Brain Res 1462:93–99. doi:10.1016/j.brainres.2012.02.051 PubMedCentralCrossRefPubMed

58.

Wu CY, Whye D, Glazewski L, Choe L, Kerr D, Lee KH, Mason RW, Wang W (2011) Proteomic assessment of a cell model of spinal muscular atrophy. BMC Neurosci 12:25. doi:10.1186/1471-2202-12-25 PubMedCentralCrossRefPubMed

59.

Yamazaki T, Chen S, Yu Y, Yan B, Haertlein TC, Carrasco MA, Tapia JC, Zhai B, Das R, Lalancette-Hebert M, Sharma A, Chandran S, Sullivan G, Nishimura AL, Shaw CE, Gygi SP, Shneider NA, Maniatis T, Reed R (2012) FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell rep 2:799–806. doi:10.1016/j.celrep.2012.08.025 PubMedCentralCrossRefPubMed

60.

Zhang Z, Pinto AM, Wan L, Wang W, Berg MG, Oliva I, Singh LN, Dengler C, Wei Z, Dreyfuss G (2013) Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. Proc Natl Acad Sci U S A 110:19348–19353. doi:10.1073/pnas.1319280110 PubMedCentralCrossRefPubMed

Title: Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn 2b/- mouse model of spinal muscular atrophy
Authors: Lyndsay M. Murray
Ariane Beauvais
Sabrina Gibeault
Natalie L. Courtney
Rashmi Kothary
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2015
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-015-0231-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn ^2b/- mouse model of spinal muscular atrophy

Abstract

Introduction

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Results

Conclusions

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