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Using Systems Biology and Mathematical Modeling Approaches in the Discovery of Therapeutic Targets for Spinal Muscular Atrophy

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Systems Neuroscience

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 21))

Abstract

Systems biology uses a combination of experimental and mathematical approaches to investigate the complex and dynamic interactions with a given system or biological process. Systems biology integrates genetics, signal transduction, biochemistry and cell biology with mathematical modeling. It can be used to identify novel pathways implicated in diseases as well as to understand the mechanisms by which a specific gene is regulated. This review describes the development of mathematical models for the regulation of an endogenous modifier gene, SMN2, in spinal muscular atrophy—an early-onset motor neuron disease that is a leading genetic cause of infant mortality worldwide—by cAMP signaling. These mathematical models not only can aid in understanding how SMN2 expression is regulated but they can also be used to examine the best ways to manipulate cAMP signaling to maximally increase SMN2 expression. These models will lead to the development of therapeutic strategies for treating SMA. This systems biology approach can also be applied to other neurological diseases, particularly those in which a disease-causing gene or a modifier gene has been identified.

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Abbreviations

AC:

Adenylate cyclase

cAMP:

Cyclic AMP

cnPDE:

Cyclic nucleotide phosphodiesterase

CRE:

cAMP-response element

CREB:

CRE binding protein

dbcAMP:

Dibutyryl cAMP

ELISA:

Enzyme-linked immunosorbent assay

ESS:

Exonic splicing enhancer

FL-SMN:

Full length SMN

GPCR:

G protein-coupled receptor

IGF1R:

Insulin-like growth factor 1 receptor

ODE:

Ordinary differential equation

PDE:

Partial differential equation

PKA:

cAMP-dependent protein kinase

PP2A:

Protein phosphatase 2A

SMA:

Spinal muscular atrophy

SMN1 :

Survival motor neuron 1

SMN2 :

Survival motor neuron 2

SMNΔ7:

SMN lacking exon 7

SNV:

Single nucleotide variant

References

  • Andreassi C, Angelozzi C, Tiziano FD, Vitali T, De Vincenzi E, Boninsegna A, et al. Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. Eur J Hum Genet. 2004;12:59–65.

    Article  CAS  Google Scholar 

  • Andreassi C, Jarecki J, Zhou J, Coovert DD, Monani UR, Chen X, et al. Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Hum Mol Genet. 2001;10:2841–9.

    Article  CAS  Google Scholar 

  • Angelozzi C, Borgo F, Tiziano FD, Martella A, Neri G, Brahe C. Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells. J Med Genet. 2008;45:29–31.

    Article  CAS  Google Scholar 

  • Ay A, Arnosti DN. Mathematical modeling of gene expression: a guide for the perplexed biologist. Crit Rev Biochem Mol Biol. 2011;46:137–51.

    Article  Google Scholar 

  • Banga JR, Balsa-Canto E. Parameter estimation and optimal experimental design. Essays Biochem. 2008;45:195.

    Article  CAS  Google Scholar 

  • Ben-Shachar S, Orr-Urtreger A, Bardugo E, Shomrat R, Yaron Y. Large-scale population screening for spinal muscular atrophy: clinical implications. Genet Med. 2011;13:110–4.

    Article  Google Scholar 

  • Bernal S, Alías L, Barceló MJ, Also-Rallo E, Martínez-Hernández R, Gámez J, et al. The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. J Med Genet. 2010;47:640–2.

    Article  CAS  Google Scholar 

  • Bevan AK, Hutchinson KR, Foust KD, Braun L, McGovern VL, Schmelzer L, et al. Early heart failure in the SMNΔ7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. Hum Mol Genet. 2010;19:3895–905.

    Article  CAS  Google Scholar 

  • Biondi O, Branchu J, Ben Salah A, Houdebine L, Bertin L, Chali F, et al. IGF-1R reduction triggers neuroprotective signaling pathways in spinal muscular atrophy mice. J Neurosci. 2015;35:12063–79.

    Article  CAS  Google Scholar 

  • Biondi O, Branchu J, Sanchez G, Lancelin C, Deforges S, Lopes P, et al. In vivo NMDA receptor activation accelerates motor unit maturation, protects spinal motor neurons and enhances SMN2 gene expression in severe spinal muscular atrophy mice. J Neurosci. 2010;30:11288–99.

    Article  CAS  Google Scholar 

  • Biondi O, Lopes P, Desseille C, Branchu J, Chali F, Ben Salah A, et al. Physical exercise reduces cardiac defects in type 2 spinal muscular atrophy-like mice. J Physiol. 2012;590:5907–25.

    Article  CAS  Google Scholar 

  • Bowerman M, Michalski JP, Beauvais A, Murray LM, DeRepentigny Y, Kothary R. Defects in pancreatic development and glucose metabolism in SMN-depleted mice independent of canonical spinal muscular atrophy neuromuscular pathology. Hum Mol Genet. 2014;23:3432–44.

    Article  CAS  Google Scholar 

  • Bowerman M, Swoboda KJ, Michalski JP, Wang GS, Reeks C, Beauvais A, et al. Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann Neurol. 2012;72:256–68.

    Article  CAS  Google Scholar 

  • Branchu J, Biondi O, Chali F, Collin T, Leroy F, Mamchaoui K, et al. Shift from extracellular signal-related kinase to AKT/cAMP response element-binding protein pathway increases survival-motor-neuron expression in spinal-muscular-atrophy-like mice and patient cells. J Neurosci. 2013;33:4280–94.

    Article  CAS  Google Scholar 

  • Burnett BG, Muñoz E, Tandon A, Kwon DY, Sumner CJ, Fischbeck KH. Regulation of SMN protein stability. Mol Cell Biol. 2009;29:1107–15.

    Article  CAS  Google Scholar 

  • Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7.

    Article  Google Scholar 

  • Butchbach MER, Burghes AHM. Perspectives on models of spinal muscular atrophy for drug discovery. Drug Discov Today Dis Model. 2004;1:151–6.

    Article  CAS  Google Scholar 

  • Cherry JJ, Kobayashi DT, Lynes MM, Naryshkin NN, Tiziano FD, Zaworksi PG, et al. Assays for the identification and prioritization of drug candidates for spinal muscular atrophy. Assay Drug Dev Technol. 2014;12:315–41.

    Article  CAS  Google Scholar 

  • Cho S, Dreyfuss G. A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. Genes Dev. 2010;24:438–42.

    Article  CAS  Google Scholar 

  • Coovert DD, Le TT, McAndrew PE, Strasswimmer J, Crawford TO, Mendell JR, et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet. 1997;6:1205–14.

    Article  CAS  Google Scholar 

  • Crawford TO, Pardo CA. The neurobiology of childhood spinal muscular atrophy. Neurobiol Dis. 1996;3:97–110.

    Article  CAS  Google Scholar 

  • Cuscó I, Barceló MJ, Soler C, Parra J, Baiget M, Tizzano E. Prenatal diagnosis for risk of spinal muscular atrophy. Br J Obstet Gynaecol. 2002;109:1244–9.

    Article  Google Scholar 

  • Dhurjati P, Mahadevan R. Systems biology: the synergistics interplay between biology and mathematics. Can J Chem Eng. 2008;86:127–41.

    Article  CAS  Google Scholar 

  • Funahashi A, Morohashi M, Kitano H, Tanimura N. CellDesigner: a process diagram editor for gene-regulatory and biochemical networks. Biosilico. 2003;1:159–62.

    Article  Google Scholar 

  • Gombash SE, Cowley CJ, Fitzgerald JA, Iyer CC, Fried D, McGovern VL, et al. SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice. Hum Mol Genet. 2015;24:3847–60.

    Article  CAS  Google Scholar 

  • Grzeschik SM, Ganta M, Prior TW, Heavlin WD, Wang CH. Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells. Ann Neurol. 2005;58:194–202.

    Article  CAS  Google Scholar 

  • Hao Le T, Burghes AHM, Beattie CE. Generation and characterization of a genetic zebrafish model of SMA carrying the human SMN2 gene. Mol Neurodegener. 2011;6:24.

    Article  CAS  Google Scholar 

  • Harahap NIF, Nurputra DK, Rochmah MA, Shima A, Morisada N, Takarada T, et al. Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells. Biochem Biophys Rep. 2015;4:351–6.

    PubMed  PubMed Central  Google Scholar 

  • Heier CR, Satta R, Lutz C, DiDonato CJ. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum Mol Genet. 2010;19:3906–18.

    Article  CAS  Google Scholar 

  • Hendrickson BC, Donohoe C, Akmaev VR, Sugarman EA, Labrousse P, Boguslavskiy L, et al. Differences in SMN1 allele frequencies among ethnic groups within North America. J Med Genet. 2009;46:641–4.

    Article  CAS  Google Scholar 

  • Hoops S, Sahle S, Gauges R, Lee C, Pahle J, Simus N, et al. COPASI—a complex pathway simulator. Bioinformatics. 2006;22:3067–74.

    Article  CAS  Google Scholar 

  • 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;24:66–70.

    Article  CAS  Google Scholar 

  • Hucka M, Finney A, Sauro HM, Bolouri H, Doyle JC, Kitano H, et al. The systems biology markup language (SBML): a medium for representaion and exchange of biochemical network models. Bioinformatics. 2003;19:524–31.

    Article  CAS  Google Scholar 

  • Ingalls B. Sensitivity analysis: from model parameters to system behaviour. Essays Biochem. 2008;45:177–93.

    Article  CAS  Google Scholar 

  • Jarecki J, Chen X, Bernardino A, Coovert DD, Whitney M, Burghes AHM, et al. Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy. Hum Mol Genet. 2005;14:2003–18.

    Article  CAS  Google Scholar 

  • Kleppe R, Krakstad C, Selheim F, Kopperud R, Døskeland SO. The cAMP-dependent protein kinase pathway as therapeutic target—possibilities and pitfalls. Curr Top Med Chem. 2011;11:1393–405.

    Article  CAS  Google Scholar 

  • Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015;33:831–46.

    Article  Google Scholar 

  • Labrum R, Rodda J, Krause A. The molecular basis of spinal muscular atrophy (SMA) in South African black patients. Neuromuscul Disord. 2007;17:684–92.

    Article  CAS  Google Scholar 

  • Le Novère N. Quantitative and logic modelling of molecular and gene networks. Nat Rev Genet. 2015;16:146–58.

    Article  Google Scholar 

  • Le Novère N, Hucka M, Mi H, Moodie S, Schreiber F, Sorokin A, et al. The systems biology graphical notation. Nat Biotechnol. 2009;27:735–41.

    Article  Google Scholar 

  • Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80:155–65.

    Article  CAS  Google Scholar 

  • Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. EMBO J. 1996;15:3555–65.

    Article  CAS  Google Scholar 

  • Lorson CL, Androphy EJ. An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet. 2000;9:259–65.

    Article  CAS  Google Scholar 

  • 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 U S A. 1999;96:6307–11.

    Article  CAS  Google Scholar 

  • Lunn MR, Root DE, Martino AM, Flaherty SP, Kelley BP, Coovert DD, et al. Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism. Chem Biol. 2004;11:1489–93.

    Article  CAS  Google Scholar 

  • Lyahyai J, Sbiti A, Barkat A, Ratbi I, Sefiani A. Spinal muscular atrophy carrier frequency and estimated prevalence of the disease in Moroccan newborns. Genet Test Mol Biomarkers. 2012;16:215–8.

    Article  CAS  Google Scholar 

  • Mack SG, Cook DJ, Dhurjati P, Butchbach MER. Systems biology investigation of cAMP modulation to increase SMN levels for treatment of spinal muscular atrophy. PLoS One. 2014;9:e115473.

    Article  Google Scholar 

  • MacLean AL, Harrington HA, Stumpf MPH, Byrne HM. Mathematical and statistical techniques for systems medicine: the Wnt signaling pathway as a case study. Methods Mol Biol. 2016;1386:405–39.

    Article  CAS  Google Scholar 

  • Majumder S, Varadharaj S, Ghoshal K, Monani U, Burghes AHM, Jacob ST. Identification of a novel cyclic AMP response element (CRE-II) and the role of CREB-1 in the cAMP-induced expression of the survival motor neuron (SMN) gene. J Biol Chem. 2004;279:14803–11.

    Article  CAS  Google Scholar 

  • Mattis VB, Rai R, Wang J, Chang CWT, Coady T, Lorson CL. Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts. Hum Genet. 2006;120:589–601.

    Article  CAS  Google Scholar 

  • Mendes P, Hoops S, Sahle S, Gauges R, Dada J, Kummer U. Computational models of biochemical networks using COPASI. Methods Mol Biol. 2009;500:17–59.

    Article  CAS  Google Scholar 

  • Michaud M, Arnoux T, Bielli S, Durand E, Rotrou Y, Jablonka S, et al. Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy. Neurobiol Dis. 2010;38:125–35.

    Article  Google Scholar 

  • Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AHM, et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 1999;8:1177–83.

    Article  CAS  Google Scholar 

  • 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;9:333–9.

    Article  CAS  Google Scholar 

  • Munsat TL, Davies KE. International SMA consortium meeting. Neuromuscul Disord. 1992;2:423–8.

    Article  CAS  Google Scholar 

  • Novoyatleva T, Heinrich B, Tang Y, Benderska N, Butchbach MER, Lorson CL, et al. Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing. Hum Mol Genet. 2008;17:52–70.

    Article  CAS  Google Scholar 

  • Pearn J. Incidence, prevalence and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet. 1978;15:409–13.

    Article  CAS  Google Scholar 

  • Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 2009;85:408–13.

    Article  CAS  Google Scholar 

  • Riessland M, Brichta L, Hahnen E, Wirth B. The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells. Hum Genet. 2006;120:101–10.

    Article  CAS  Google Scholar 

  • Rochette CF, Gilbert N, Simard LR. SMN gene duplication and emergence of the SMN2 gene occured in distinct hominids: SMN2 is unique to Homo sapiens. Hum Genet. 2001;108:255–66.

    Article  CAS  Google Scholar 

  • Russman BS. Spinal muscular atrophy: clinical classification and disease heterogeneity. J Child Neurol. 2007;22:946–51.

    Article  Google Scholar 

  • Ryll A, Bucher J, Bonin A, Bongard S, Gonçalves E, Saez-Rodriguez J, et al. A model integration approach linking signalling and gene-regulatory logic with kinetic metabolic models. Biosystems. 2014;124:26–38.

    Article  CAS  Google Scholar 

  • Sangaré M, Hendrickson B, Sango HA, Chen K, Nofziger J, Amara A, et al. Genetics of low spinal muscular atrophy carrier frequency in sub-Saharan Africa. Ann Neurol. 2014;75:525–32.

    Article  Google Scholar 

  • Schmidt H, Jirstrand M. Systems Biology Toolbox for MATLAB: a computational platform for research in systems biology. Bioinformatics. 2006;22:514–5.

    Article  CAS  Google Scholar 

  • Schrank B, Götz 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;94:9920–5.

    Article  CAS  Google Scholar 

  • Shababi M, Habibi J, Ma L, Glascock JJ, Sowers JR, Lorson CL. Partial restoration of cardio-vascular defects in a rescued severe model of spinal muscular atrophy. J Mol Cell Cardiol. 2012;52:1074–82.

    Article  CAS  Google Scholar 

  • Shababi M, Habibi J, Yang HT, Vale SM, Sewell WA, Lorson CL. Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum Mol Genet. 2010;19:4059–71.

    Article  CAS  Google Scholar 

  • Shababi M, Lorson CL, Rudnik-Schöneborn S. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2014;224:15–28.

    Article  CAS  Google Scholar 

  • Su YN, Hung CC, Lin SY, Chen FY, Chern JPS, Tsai C, et al. Carrier screening for spinal muscular atrophy (SMA) in 107,611 pregnant women during the period 2005-2009: a prospective population-based cohort study. PLoS One. 2011;6:e17067.

    Article  CAS  Google Scholar 

  • Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs AM, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of > 72400 specimens. Eur J Hum Genet. 2012;20:27–32.

    Article  Google Scholar 

  • Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, Coovert DD, et al. Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol. 2003;54:647–54.

    Article  CAS  Google Scholar 

  • Thurmond J, Butchbach MER, Palomo M, Pease B, Rao M, Bedell L, et al. Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy. J Med Chem. 2008;51:449–69.

    Article  CAS  Google Scholar 

  • Tiziano FD, Lomastro R, Pinto AM, Messina S, D'Amico A, Fiori S, et al. Salbutamol increases survival motor neuron (SMN) transcript levels in leukocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design. J Med Genet. 2010;47:856–8.

    Article  CAS  Google Scholar 

  • Vezain M, Saukkonen AM, Goina E, Touraine R, Manel V, Toutain A, et al. A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy. Hum Mutat. 2010;31:E1110–25.

    Article  Google Scholar 

  • Villoslada P, Steinman L, Baranzini SE. Systems biology and its application to the understanding of neurological diseases. Ann Neurol. 2009;65:124–39.

    Article  CAS  Google Scholar 

  • Wadzinski BE, Wheat WH, Jaspers S, Peruski LF Jr, Lickteig RL, Johnson GL, et al. Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. Mol Cell Biol. 1993;13:2822–34.

    Article  CAS  Google Scholar 

  • Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22:1027–49.

    Article  Google Scholar 

  • Williamson T, Schwartz JM, Kell DB, Stateva L. Deterministic mathematical models of the cAMP pathway in Saccharomyces cerevisiae. BMC Syst Biol. 2009;3:70.

    Article  Google Scholar 

  • Wu CY, Curtis A, Choi Y, Maeda M, Xu MJ, Berg A, et al. Identification of the phosphorylation sites in the survival motor neuron protein by protein kinase A. Biochim Biophys Acta. 2011;1814:1134–9.

    Article  CAS  Google Scholar 

  • Xiao J, Marugan JJ, Zheng W, Titus S, Southall N, Cherry JJ, et al. Discovery, synthesis and biological evaluation of novel SMN protein modulators. J Med Chem. 2011;54:6215–33.

    Article  CAS  Google Scholar 

  • Zaldívar T, Montejo Y, Acevedo AM, Guerra R, Vargas J, Garofalo N, et al. Evidence of reduced frequency of spinal muscular atrophy type I in the Cuban population. Neurology. 2005;65:636–8.

    Article  Google Scholar 

  • Zhang Z, Keleman O, Van Santen MA, Yelton SM, Wendlandt AE, Sviripa VM, et al. Synthesis and characterization of pseudocantharidins, novel phosphatase modulators that promote the inclusion of exon 7 into the SMN (survival of motoneuron) pre-mRNA. J Biol Chem. 2011;286:10126–36.

    Article  CAS  Google Scholar 

  • Zi Z. A tutorial on mathematical modeling of biological signaling pathways. Methods Mol Biol. 2012;880:41–51.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (P30GM114736) and by the Nemours Foundation.

Conflict of Interest

The author declares no conflict of interest.

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Authors and Affiliations

  1. Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA

    Matthew E. R. Butchbach

  2. Center for Pediatric Research, Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA

    Matthew E. R. Butchbach

  3. Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA

    Matthew E. R. Butchbach

  4. Department of Biological Sciences, University of Delaware, Newark, DE, USA

    Matthew E. R. Butchbach

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Correspondence to Matthew E. R. Butchbach .

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  1. Neuroscience Research Institute, Peking University, Beijing, China

    Albert Cheung-Hoi Yu

  2. Neuroscience Research Institute, Peking University, Beijing, China

    Lina Li

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Butchbach, M.E.R. (2018). Using Systems Biology and Mathematical Modeling Approaches in the Discovery of Therapeutic Targets for Spinal Muscular Atrophy. In: Cheung-Hoi Yu, A., Li, L. (eds) Systems Neuroscience. Advances in Neurobiology, vol 21. Springer, Cham. https://doi.org/10.1007/978-3-319-94593-4_10

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