Neuromuscular effects of G93A-SOD1 expression in zebrafish

Molecular Neurodegeneration

Eva L Feldman²  James J Dowling¹  Stephen G Philip²  Andrew A Rosenberg²  Madeline Palmer²  Grettel Zamora-Berridi²  Sang Su Oh²  Angela S Busta¹  J Simon Lunn²  Stacey A Sakowski² 

[1] Department of Pediatrics & Communicable Diseases, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, 5019 AAT-BSRB, MI, USA;Department of Neurology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, 5017 AAT-BSRB, MI, USA

关键词: Neurodegeneration;    Neuromuscular junction;    G93A-SOD1;    Cu²⁺/Zn²⁺ superoxide dismutase (SOD1);    Zebrafish;    Motor neuron (MN);    Amyotrophic lateral sclerosis (ALS);   

Others  :  863776
DOI  :  10.1186/1750-1326-7-44

 received in 2012-02-24, accepted in 2012-08-26,  发布年份 2012

【 摘 要 】

Background

Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis.

Results

We demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease.

Conclusions

This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.

【 授权许可】

   
2012 Sakowski et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Boillee S, Vande Velde C, Cleveland DW: ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 2006, 52:39-59.
• [2]Ilieva H, Polymenidou M, Cleveland DW: Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol 2009, 187:761-772.
• [3]Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD: Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 2004, 185:232-240.
• [4]Fischer LR, Glass JD: Axonal degeneration in motor neuron disease. Neurodegener Dis 2007, 4:431-442.
• [5]Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, et al.: DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 2004, 74:1128-1135.
• [6]Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, et al.: ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet 2006, 38:411-413.
• [7]Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, et al.: A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001, 29:166-173.
• [8]Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, et al.: Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009, 323:1205-1208.
• [9]Lagier-Tourenne C, Cleveland DW: Rethinking ALS: the FUS about TDP-43. Cell 2009, 136:1001-1004.
• [10]Munch C, Sedlmeier R, Meyer T, Homberg V, Sperfeld AD, Kurt A, Prudlo J, Peraus G, Hanemann CO, Stumm G, Ludolph AC: Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology 2004, 63:724-726.
• [11]Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, et al.: A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 2004, 75:822-831.
• [12]Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, et al.: Mutant dynactin in motor neuron disease. Nat Genet 2003, 33:455-456.
• [13]Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, et al.: Mutations in Cu/Zn superoxide dismutase are associated with familial amyotrophic lateral sclerosis. Nature 1993, 362:59-62.
• [14]Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, et al.: The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 2001, 29:160-165.
• [15]Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, et al.: Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 2011, 477:211-215.
• [16]Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, et al.: Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010, 465:223-226.
• [17]DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, et al.: Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011, 72:245-256.
• [18]Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, et al.: A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011, 72:257-268.
• [19]Joyce PI, Fratta P, Fisher EM, Acevedo-Arozena A: SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments. Mamm Genome 2011, 22:420-448.
• [20]Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM: Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 2000, 288:335-339.
• [21]Lunn JS, Sakowski SA, Kim B, Rosenberg AA, Feldman EL: Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration. Dev Neurobiol 2009, 69:871-884.
• [22]Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994, 264:1772-1775.
• [23]Peviani M, Caron I, Pizzasegola C, Gensano F, Tortarolo M, Bendotti C: Unraveling the complexity of amyotrophic lateral sclerosis: recent advances from the transgenic mutant SOD1 mice. CNS Neurol Disord Drug Targets 2010, 9:491-503.
• [24]Dadon-Nachum M, Melamed E, Offen D: The "dying-back" phenomenon of motor neurons in ALS. J Mol Neurosci 2011, 43:470-477.
• [25]Dupuis L, Loeffler JP: Neuromuscular junction destruction during amyotrophic lateral sclerosis: insights from transgenic models. Curr Opin Pharmacol 2009, 9:341-346.
• [26]Kabashi E, Brustein E, Champagne N, Drapeau P: Zebrafish models for the functional genomics of neurogenetic disorders. Biochim Biophys Acta 2011, 1812:335-345.
• [27]Kabashi E, Champagne N, Brustein E, Drapeau P: In the swim of things: recent insights to neurogenetic disorders from zebrafish. Trends Genet 2010, 26:373-381.
• [28]Flanagan-Steet H, Fox MA, Meyer D, Sanes JR: Neuromuscular synapses can form in vivo by incorporation of initially aneural postsynaptic specializations. Development 2005, 132:4471-4481.
• [29]Higashijima S, Okamoto H, Ueno N, Hotta Y, Eguchi G: High-frequency generation of transgenic zebrafish which reliably express GFP in whole muscles or the whole body by using promoters of zebrafish origin. Dev Biol 1997, 192:289-299.
• [30]Kim MJ, Kang KH, Kim CH, Choi SY: Real-time imaging of mitochondria in transgenic zebrafish expressing mitochondrially targeted GFP. Biotechniques 2008, 45:331-334.
• [31]Meng A, Tang H, Ong BA, Farrell MJ, Lin S: Promoter analysis in living zebrafish embryos identifies a cis-acting motif required for neuronal expression of GATA-2. Proc Natl Acad Sci USA 1997, 94:6267-6272.
• [32]Boon KL, Xiao S, McWhorter ML, Donn T, Wolf-Saxon E, Bohnsack MT, Moens CB, Beattie CE: Zebrafish survival motor neuron mutants exhibit presynaptic neuromuscular junction defects. Hum Mol Genet 2009, 18:3615-3625.
• [33]le Hao T, Burghes AH, Beattie CE: Generation and Characterization of a genetic zebrafish model of SMA carrying the human SMN2 gene. Mol Neurodegener 2011, 6:24. BioMed Central Full Text
• [34]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, 162:919-931.
• [35]Kabashi E, Bercier V, Lissouba A, Liao M, Brustein E, Rouleau GA, Drapeau P: FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis. PLoS Genet 2011, 7:e1002214.
• [36]Lemmens R, Van Hoecke A, Hersmus N, Geelen V, D'Hollander I, Thijs V, Van Den Bosch L, Carmeliet P, Robberecht W: Overexpression of mutant superoxide dismutase 1 causes a motor axonopathy in the zebrafish. Hum Mol Genet 2007, 16:2359-2365.
• [37]Gros-Louis F, Kriz J, Kabashi E, McDearmid J, Millecamps S, Urushitani M, Lin L, Dion P, Zhu Q, Drapeau P, et al.: Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish. Hum Mol Genet 2008, 17:2691-2702.
• [38]Simpson CL, Lemmens R, Miskiewicz K, Broom WJ, Hansen VK, van Vught PW, Landers JE, Sapp P, Van Den Bosch L, Knight J, et al.: Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum Mol Genet 2009, 18:472-481.
• [39]Kabashi E, Lin L, Tradewell ML, Dion PA, Bercier V, Bourgouin P, Rochefort D, Bel Hadj S, Durham HD, Vande Velde C, et al.: Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum Mol Genet 2010, 19:671-683.
• [40]Ramesh T, Lyon AN, Pineda RH, Wang C, Janssen PM, Canan BD, Burghes AH, Beattie CE: A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease. Dis Model Mech 2010, 3:652-662.
• [41]Sakowski SA, Schuyler AD, Feldman EL: Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2009, 10:63-73.
• [42]Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P: Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci 2000, 20:2534-2542.
• [43]Gould TW, Buss RR, Vinsant S, Prevette D, Sun W, Knudson CM, Milligan CE, Oppenheim RW: Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS. J Neurosci 2006, 26:8774-8786.
• [44]Sagot Y, Dubois-Dauphin M, Tan SA, de Bilbao F, Aebischer P, Martinou JC, Kato AC: Bcl-2 overexpression prevents motoneuron cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease. J Neurosci 1995, 15:7727-7733.
• [45]Sakowski SA, Heavener SB, Lunn JS, Fung K, Oh SS, Spratt SK, Hogikyan ND, Feldman EL: Neuroprotection using gene therapy to induce vascular endothelial growth factor-A expression. Gene Ther 2009, 16:1292-1299.
• [46]Dupuis L, Echaniz-Laguna A: Skeletal muscle in motor neuron diseases: therapeutic target and delivery route for potential treatments. Curr Drug Targets 2010, 11:1250-1261.
• [47]Kwan KM, Fujimoto E, Grabher C, Mangum BD, Hardy ME, Campbell DS, Parant JM, Yost HJ, Kanki JP, Chien CB: The Tol2kit: a multisite gateway-based construction kit for Tol2 transposon transgenesis constructs. Dev Dyn 2007, 236:3088-3099.
• [48]Kawakami K, Takeda H, Kawakami N, Kobayashi M, Matsuda N, Mishina M: A transposon-mediated gene trap approach identifies developmentally regulated genes in zebrafish. Dev Cell 2004, 7:133-144.
• [49]Mancuso R, Olivan S, Osta R, Navarro X: Evolution of gait abnormalities in SOD1(G93A) transgenic mice. Brain Res 2011, 1406:65-73.
• [50]Rubin A, Mobley B, Hogikyan N, Bell K, Sullivan K, Boulis N, Feldman E: Delivery of an adenoviral vector to the crushed recurrent laryngeal nerve. Laryngoscope 2003, 113:985-989.
• [51]Jang YC, Lustgarten MS, Liu Y, Muller FL, Bhattacharya A, Liang H, Salmon AB, Brooks SV, Larkin L, Hayworth CR, et al.: Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration. FASEB J 2010, 24:1376-1390.
• [52]Hirata H, Watanabe T, Hatakeyama J, Sprague SM, Saint-Amant L, Nagashima A, Cui WW, Zhou W, Kuwada JY: Zebrafish relatively relaxed mutants have a ryanodine receptor defect, show slow swimming and provide a model of multi-minicore disease. Development 2007, 134:2771-2781.
• [53]Lefebvre JL, Jing L, Becaficco S, Franzini-Armstrong C, Granato M: Differential requirement for MuSK and dystroglycan in generating patterns of neuromuscular innervation. Proc Natl Acad Sci USA 2007, 104:2483-2488.
• [54]Panzer JA, Song Y, Balice-Gordon RJ: In vivo imaging of preferential motor axon outgrowth to and synaptogenesis at prepatterned acetylcholine receptor clusters in embryonic zebrafish skeletal muscle. J Neurosci 2006, 26:934-947.
• [55]Saint-Amant L, Sprague SM, Hirata H, Li Q, Cui WW, Zhou W, Poudou O, Hume RI, Kuwada JY: The zebrafish ennui behavioral mutation disrupts acetylcholine receptor localization and motor axon stability. Dev Neurobiol 2008, 68:45-61.
• [56]Panzer JA, Gibbs SM, Dosch R, Wagner D, Mullins MC, Granato M, Balice-Gordon RJ: Neuromuscular synaptogenesis in wild-type and mutant zebrafish. Dev Biol 2005, 285:340-357.
• [57]Wong M, Martin LJ: Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet 2010, 19:2284-2302.
• [58]Reimer MM, Sorensen I, Kuscha V, Frank RE, Liu C, Becker CG, Becker T: Motor neuron regeneration in adult zebrafish. J Neurosci 2008, 28:8510-8516.
• [59]Maures T, Chan SJ, Xu B, Sun H, Ding J, Duan C: Structural, biochemical, and expression analysis of two distinct insulin-like growth factor I receptors and their ligands in zebrafish. Endocrinology 2002, 143:1858-1871.
• [60]Dowling JJ, Gibbs E, Russell M, Goldman D, Minarcik J, Golden JA, Feldman EL: Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function. Circ Res 2008, 102:423-431.
• [61]Dowling JJ, Vreede AP, Low SE, Gibbs EM, Kuwada JY, Bonnemann CG, Feldman EL: Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy. PLoS Genet 2009, 5:e1000372.
• [62]Westerfield M: The Zebrafish Book: A Guide for the Laboratory Use of Zebrafish (Danio rerio). 5th edition. Eugene, OR: The University of Oregon Press; 2007.
• [63]Dowling JJ, Gibbs EM, Feldman EL: Membrane traffic and muscle: lessons from human disease. Traffic 2008, 9:1035-1043.
• [64]Rouaux C, Panteleeva I, Rene F, de Aguilar JL G, Echaniz-Laguna A, Dupuis L, Menger Y, Boutillier AL, Loeffler JP: Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. J Neurosci 2007, 27:5535-5545.
• [65]Rubin AD, Hogikyan ND, Sullivan K, Boulis N, Feldman EL: Remote delivery of rAAV-GFP to the rat brainstem through the recurrent laryngeal nerve. Laryngoscope 2001, 111:2041-2045.
• [66]Kim H, Kim HY, Choi MR, Hwang S, Nam KH, Kim HC, Han JS, Kim KS, Yoon HS, Kim SH: Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci Lett 2010, 468:190-194.
• [67]Boulis NM, Turner DE, Imperiale MJ, Feldman EL: Neuronal survival following remote adenovirus gene delivery. J Neurosurg 2002, 96:212-219.