Matthew E. R. Butchbach, Ph.D.

Research Interests

The overall goals of the Motor Neuron Diseases Research Laboratory (MNDRL) are to understand the mechanisms that cause motor neurons to degenerate. We use multiple approaches and techniques—including those based in biochemistry, genetics, cell biology, neuroanatomy, pharmacology, behavior and mathematical biology—to study neurodegeneration and neuroprotection. Our research requires the development and use of multiple model systems for motor neurons. We then use this information to develop and test novel therapeutic strategies to help prevent motor neuron degeneration. Since our primary affiliation is with a pediatric hospital, we primarily focus on early-onset motor neuron diseases such as spinal muscular atrophy (SMA)—a leading genetic cause of infant death in the world, distal hereditary motor neuropathies (HMNs) and certain forms of amyotrophic lateral sclerosis (ALS). Our approaches can also be applied to other neurodegenerative diseases as well as to acquired neuronal injury. In addition to our work on motor neuron diseases, we are exploring the mechanisms underlying glutamate-induced neurotoxicity, or excitotoxicity, in motor neurons and developing ways to prevent excitotoxic neuronal death.

Development of Neuroprotective Therapeutic Strategies for Motor Neuron Disease
Spinal muscular atrophy (SMA) is a leading genetic cause of infant death in the world. SMA is the result of reduced expression of SMN protein. In humans there are two nearly identical copies of the SMN gene (SMN1 and SMN2). There is a C-to-T transition in exon 7 of SMN2 that alters a splicing regulatory element which leads to reduced inclusion of exon 7 in SMN2-derived transcripts and, hence, reduced levels of SMN protein. In SMA, SMN1 (which produces full-length SMN protein) is lost while SMN2 is retained. SMN gene replacement using gene therapy vectors and modulation of SMN expression by drug compounds have been shown to improve the survival and phenotypes of various mouse models of SMA. Studies using transgenic mice have shown that increasing SMN2 copy number improves the survival and phenotype of SMA mouse models. Likewise, in humans, patients with a higher the SMN2 copy number generally have the milder the SMA phenotype. These observations collectively suggest that SMN2 may be a therapeutic target for SMA. In this project, we will generate novel methods to monitor SMN2 induction and exon 7 inclusion in the spinal cord of living SMA mice. This information will be extremely useful in understanding the effectiveness of SMN-inducing drugs in treating SMA and will lead to the design of newer drugs with better protective properties.

Butyrate-based compounds such as phenylbutyrate have been suggested to be potential drug compounds for treating SMA patients. These compounds improve survival of a mouse model of SMA but do not increase SMN in the spinal cord. Work from others has shown that administration of 4-phenylbutyrate to SOD1(G93A) amyotrophic lateral sclerosis (ALS) transgenic mice improves their survival by ~21%. In this project, we propose to test butyrate-based compounds in transgenic mouse models for motor neuron diseases such as SMA, ALS and SMA with respiratory distress 1 (SMARD1). We will also determine the mechanism(s) by which these compounds exert their neuroprotective effects. These compounds, therefore, will be more potent therapeutics for motor neuron diseases which can be moved forward into clinical trials.

Establishment of Cell Culture Models for Early-Onset Motor Neuron DiseasesThe identification of therapeutic agents for early-onset motor neuron diseases (MNDs) like SMA is driven by the use of skin fibroblasts as an in cellulo model. Unfortunately, therapeutics identification in this manner has met with limited success because some compounds which increase SMN protein—the defective protein in SMA—in fibroblasts do not increase SMN expression in vivo in motor neurons. It is, therefore, desirable to have a cellular model of SMA motor neurons for dissecting the mechanisms of motor neuron loss in SMA as well as for testing the efficacies of novel therapeutics. Somatic cells such as fibroblasts can be transformed into pluripotent cells (creating induced pluripotent stem cells (iPSCs)) that are capable of being differentiated into many types of cells—including motor neurons. In this project, we propose to generate iPS cell lines from our collection of fibroblasts from MND patients with varying phenotypes. We will also be establishing and characterizing mouse embryonic stem cell (mESC) lines from different models for SMA as well as other early onset motor MNDs. These iPSC and mESC lines will then be differentiated into motor neurons and compared against motor neurons from normal iPSC and mESC lines. With a collection of MND stem cell lines, we will ultimately be able to, in future studies, investigate the mechanisms of disease in affected motor neurons, identify genes and transcripts that modulate disease severity and test therapeutic agents for efficacy in affected motor neurons.

Characterization of Ribonucleoprotein Complexes in Motor Neuron Axons
Deficiency of SMN in motor neurons is known to cause SMA, however, the underlying biochemical reason that motor neurons degenerate is not known. SMN is required for the assembly of small nuclear ribonucleoprotein (snRNP) complexes which function as the machinery for splicing. It has been suggested that there is a greater sensitivity of motor neurons to reduced snRNP assembly; however, this may not be the case as recent data suggests that some SMN mutations from severe SMA patients are capable of normal snRNP biogenesis but cannot rescue abnormal motor neuron axon pathfinding seen in zebrafish embryos with reduced SMN levels. SMN macromolecular complexes within motor neuron axons are critical for the normal functioning of neurons; however, this function is not yet known nor is the composition of these axonal SMN complexes. It is critical that we understand the composition of axonal SMN complexes. The other components of these axonal SMN macromolecular complexes, however, need to first be identified. Subcellular fractionation, coimmunoprecipitation and confocal microscopy will be used to identify the protein composition of these complexes. Once the components of the axonal SMN macromolecular complex have been identified, we will determine which components, if any, are altered in SMA by using various mouse models of SMA.

There are other motor neuron diseases aside from SMA that involve perturbation of some aspect of RNA metabolism. Examples of such diseases include SMA with respiratory distress (SMARD1; IGHMBP2), various familial forms of ALS (FUS/TSL and TDP-43) and lethal congenital contracture syndromes (like LCCS1; GLE1). The gene products for these familial motor neuron diseases are ubiquitously expressed but only certain cell types (i.e. motor neurons) are affected. One possible explanation for this observation is that these proteins may be involved in some aspect of RNA metabolism that is unique to neuronal processes such as axons and dendrites. To begin to address this hypothesis, we will characterize axonal RNP complexes containing IGHMBP2, FUS/TSL and TDP-43 using biochemical and cell biological approaches.

Current Projects

  • Determine the mechanism(s) of the neuroprotective effect of butyrate compounds on motor neuron diseases
  • Identification of compounds that increase SMN2 promoter activity and inclusion of exon 7
  • Development of mathematical models for regulation of SMN2 expression
  • Characterization of SMN-containing macromolecular complexes in motor neuron processes
  • Characterization of embryonic stem cell models for SMA
  • Establishment of a pediatric motor neuron diseases cell collection
  • Identification of neuroprotective agents against motor neuron excitotoxicity

Research Group

  • Matthew E. R. Butchbach, Ph.D. – principal investigator
  • Ashlee W. Harris, B.S. – research assistant II
  • Cinsley Gentillon, B.S. – graduate student, University of Delaware (M.S. Biological Sciences)
  • Andrew Connell – undergraduate student, University of Delaware
  • Ryan Kirk – undergraduate student, University of Delaware
  • Doojoon Park – undergraduate student, University of Delaware

Selected Publications

  • Mack SG, DJ Cook, P Dhurjati and MER Butchbach (2014) Systems-based study of cAMP modulation to increase SMN levels for the treatment of spinal muscular atrophy. PLoS ONE 9:e115473.
  • Maeda M, AW Harris, BF Kingham, CJ Lumpkin, LM Opdenaker, SM McCahan, W Wang and MER Butchbach (2014) Transcriptome profiling of spinal muscular atrophy motor neurons derived from mouse embryonic stem cells. 9:e106818.
  • Butchbach MER, J Singh, ME Gurney and AHM Burghes (2014) The effect of diet on the protective action of D156844 observed in spinal muscular atrophy mice. Exp Neurol 256:1-6.
  • He WA, E Berardi, VM Cardillo, S Acharyya, P Aulino, J Thomas-Ahner, J Wang, M Bloomston, P Muscarella, P Nau, N Shah, MER Butchbach, K Ladner, S Adamo, MA Rudnicki, C Keller, D Coletti, F Montanaro and DC Guttridge (2013) NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia. J Clin Invest 123:4821-4835.
  • Butchbach MER (2011) Trans-splicing, more than meets the eye: multi-faceted therapeutics for spinal muscular atrophy. [commentary] Hum Gene Ther 22:121-125.
  • Butchbach MER, J Singh, M Þorsteinsdóttir, L Saieva, E Slominski, J Thurmond, T Andrésson, J Zhang, JD Edwards, LR Simard, L Pellizzoni, AHM Burghes and ME Gurney (2010) Evaluation of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy. Hum Mol Genet 19:454-467.
  • Butchbach MER*, FF Rose Jr*, S Rhoades, J Marston, JT McCrone, R Sinnott and CL Lorson (2010) Effect of diet on the survival and phenotype of a mouse model of spinal muscular atrophy. Biochem Biophys Res Commun 391:835-840. (*these authors contributed equally)
  • VB Mattis*, MER Butchbach* and CL Lorson (2008) Detection of human survival motor neuron (SMN) protein in mice containing the Smn2 transgene: applicability to preclinical therapy development for spinal muscular atrophy. J Neurosci Methods 175:36-43. (*these authors contributed equally)
  • Thurmond J, MER Butchbach, M Palomo, B Pease, M Rao, L Bedell, M Keyvan, G Pai, R Mishra, M Haraldsson, T Andresson, G Bragason, M Thosteinsdottir, JM Bjornsson, DD Coovert, AHM Burghes, ME Gurney and J Singh (2008) 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 51:449-469.
  • Novoyatleva T, B Heinrich, Y Tang, N Benderska, MER Butchbach, CL Lorson, MA Lorson, C Ben-Dov, P Fehlbaum, L Bracco, AHM Burghes, M Bollen and S Stamm (2008) Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing. Hum Mol Genet 17:52-70.
  • Burghes AHM and MER Butchbach (2008) Let all DNA vote: who are the amyotrophic lateral sclerosis candidates? [editorial] Neurology 70:662-663.
  • Gabanella F, MER Butchbach, L Saieva, C Carrissimi, AHM Burghes and L Pellizzoni (2007) Ribonucleoprotein assembly defects correlate with SMA severity and preferentially affect a subset of spliceosomal snRNPs. PLoS ONE 2:e921.
  • Butchbach MER, JD Edwards and AHM Burghes (2007) Abnormal motor phenotype in the SMND7 mouse model of spinal muscular atrophy. Neurobiol Dis 27:207-219.
  • Butchbach MER, JD Edwards, KR Schussler and AHM Burghes (2007) A novel method for oral delivery of drug compounds to the neonatal SMND7 mouse model of spinal muscular atrophy. J Neurosci Methods 161:285-290.
  • Tian G, L Lai, H Guo, Y Lin, MER Butchbach, Y Chang and CG Lin (2007) Translational control of glial glutamate transporter EAAT2 expression. J Biol Chem 282:1727-1737.
  • Acharyya S, MER Butchbach, Z Sahenk, H Wang, M Saji, M Carathers, MD Ringel, RJE Skipsworth, KCH Fearon, MA Hollingsworth, P Muscarella, AHM Burghes, JA Rafael-Fortney and DC Guttridge (2005) Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia. Cancer Cell 8:421-432.
  • Le TT, LT Pham, MER Butchbach*, HL Zhang*, UR Monani, DD Coovert, TO Gavrilina, L Xing, GJ Bassell and AHM Burghes (2005) SMND7, the major product of the centromeric survival motor neuron gene (SMN2), extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 14:845-857. (*these authors contributed equally)
  • Butchbach MER and AHM Burghes (2004) Perspectives on models of spinal muscular atrophy for drug discovery. Drug Discov Today Dis Models 1:151-156.
  • Butchbach MER, G Tian, H Guo and CG Lin (2004) Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains: importance for EAAT localization and function. J Biol Chem 279:34388-34396.
  • Guo H*, L Lai*, MER Butchbach*, MP Stockinger*, X Shan, GA Bishop and CG Lin (2003) Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet 12:2519-2532. (*these authors contributed equally)
  • Butchbach MER, H Guo and CG Lin (2003) Methyl-b-cyclodextrin but not retinoic acid reduces EAAT3-mediated glutamate uptake and increases GTRAP3-18 expression. J Neurochem 84:891-894.
  • Guo H, L Lai, MER Butchbach and CG Lin (2002) Human glioma cells and undifferentiated primary astrocytes which express aberrant EAAT2 mRNA inhibit normal EAAT2 protein expression and prevent cell death. Mol Cell Neurosci 21:546-560.
  • Butchbach MER, L Lai and CG Lin (2002) Molecular cloning, gene structure, expression profile and functional characterization of the mouse glutamate transporter (EAAT3) interacting protein GTRAP3-18. Gene 292:81-90.

Affiliated Assistant Professor
Assistant Research Scientist II (Assistant Professor)
Head, Motor Neuron Diseases Research Laboratory, Nemours Biomedical Research
Research Assistant Professor, Department of Pediatrics, Thomas Jefferson University

Phone: (302) 298-7366

Fax: (302) 651-6539


Office: 240 Rockland Center One, Nemours/Alfred I. duPont Hospital for Children

1600 Rockland Road, Wilmington DE 19803


B.S., B.A. – Ohio University, Athens, Ohio

M.S., Ph.D. – Ohio State University, Columbus, Ohio

Postdoctoral – Ohio State University, Columbus, Ohio