Arthur Burghes

Ph.D. - University of London

Post Doctoral - University of Toronto

The main focus of the laboratory is the molecular understanding of genetic neuromuscular disorders. In particular, the laboratory focuses on unraveling the molecular biology of Spinal Muscular Atrophy (SMA). SMA is an autosomal recessive disorder that is characterized by destruction of motor neurons in the anterior horn of the spinal cord. The disorder can be classified according to clinical severity into three types. SMA is caused by loss or mutation of the SMN1 gene but not the virtually identical SMN2 gene. The two genes essentially differ by a single nucleotide that affects the incorporation of exon 7 into the SMN message. This results in the SMN2 gene producing insufficient SMN protein for motor neurons. SMN functions in the biogenesis of SnRNPs which is essential for all cells, currently it is not clear why high SMN levels are so critically important for motor neurons.

We have developed an animal model of SMA in the mouse and shown that high copy number of the SMN2 gene can rescue the SMA mouse. We are using this animal model of SMA to understand why motor neurons are affected and to develop treatments for SMA. A high throughput screen to identify compounds that can activate SMN has been started. It is hoped that these compounds can act as therapeutic reagents for SMA.

The laboratory is also developing gene therapy methods for treatment of Duchenne Muscular Dystrophy (DMD). DMD is a muscle wasting disorder caused by mutations in the large dystrophin gene. We are particularly interested in developing strategies that allow Adeno Associated Virus to be used for gene therapy of DMD.

Recent Publications:

Novoyatleva T, Heinrich B, Tang Y, Benderska N, Butchbach ME, Lorson CL, Lorson MA, Ben-Dov C, Fehlbaum P, Bracco L, Burghes AH, Bollen M and Stamm S (2007) "Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing" Hum Mol Genet. 2007 Oct 2; [Epub ahead of print]

Gabanella F, Butchbach ME, Saieva L, Carissimi C, Burghes AH and Pellizzoni L (2007) "Ribonucleoprotein Assembly Defects Correlate with Spinal Muscular Atrophy Severity and Preferentially Affect a Subset of Spliceosomal snRNPs" PLoS ONE. 2(9):e921.

Hao le T, Fuller HR, Lam le T, Le TT, Burghes AH and Morris GE (2007) "Absence of gemin5 from SMN complexes in nuclear Cajal bodies" BMC Cell Biol. 18;8:28.

Butchbach ME, Edwards JD and Burghes AH (2007) "Abnormal motor phenotype in the SMNDelta7 mouse model of spinal muscular atrophy" Neurobiol Dis. 27(2):207-19.

Butchbach ME, Edwards JD, Schussler KR and Burghes AH (2006) "A novel method for oral delivery of drug compounds to the neonatal SMNDelta7 mouse model of spinal muscular atrophy" J Neurosci Methods 161(2):285-90.

Carrel TL, McWhorter ML, Workman E, Zhang H, Wolstencroft EC, Lorson C, Bassell GJ, Burghes AHM and Beattie CE (2006) "Survival Motor Neuron Function in motor axons is independent of functions required for small nuclear ribunocleoprotein biogenesis" Neuroscience 26(43):11014-22.

Acharyya S, Butchbach ME, Sahenk Z, Wang H, Saji M, Carathers M, Ringel MD, Skipworth RJ, Fearon KC, Hollingsworth MA, Muscarella P, Burghes AH, Rafael-Fortney JA and Guttridge DC (2005) "Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia" Cancer Cell 8:421-32.

Bertini E, Burghes A, Bushby K, Estournet-Mathiaud B, Finkel RS, Hughes RA, Iannaccone ST, Melki J, Mercuri E, Muntoni F, Voit T, Reitter B, Swoboda KJ, Tiziano D, Tizzano E, Topaloglu H, Wirth B and Zerres K (2005) 134th ENMC International Workshop: Outcome Measures and Treatment of Spinal Muscular Atrophy, Naarden, The Netherlands. Neuromuscul Disord 15:802-16.

Sharma A, Lambrechts A, Hao le T, Le TT, Sewry CA, Ampe C, Burghes AH and Morris GE (2005) "A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells" Exp Cell Res 309:185-97.

Jarecki J, Chen X, Bernardino A, Coovert DD, Whitney M, Burghes A, Stack J and Pollok BA (2005) "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 14:2003-18.

Le TT, Pham LT, Butchbach ME, Zhang HL, Monani UR, Coovert DD, Gavrilina TO, Xing L, Bassell GL and Burghes AHM (2005) "SMNΔ7, 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" Human Mol Genet 14:845-57.

Mimoun A, Le T, Ralph GS, Walmsley L, Monani UR, Lee DCP, Wilkes F, Mitrophanous KA, Kingsman SM, Burghes AHM and Mazarakis ND (2004) "Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy" J Clin Invest 114:1726.

Butchbach M and Burghes A (2004) "Perspectives on models of spinal muscular atrophy for drug discovery" Drug Discov Today: Disease Models 2:151-6.

Majumder S, Varadharaj S, Ghoshal K, Monani U, Burghes AH and Jacob ST (2004) "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 279:14803-11.

Lunn MR, Root DE, Martino AM, Flaherty SP, Kelley BP, Coovert DD, Burghes AH, Nguyen TM, Morris GE, Zhou J, Androphy EJ, Sumner CJ and Stockwell BR (2004) "Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism" Chem Biol 11:1489-93.

McWhorter ML, Monani UR, Burghes AH and Beattie CE (2003) "Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding" J Cell Biol 162(5):919-31.

Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, Coovert D, Schussler K, Chen X, Jarecki J, Burghes AH, Taylor JP and Fischbeck KH (2003) "Valproic acid increases SMN levels in spinal muscular atrophy patient cells" Ann Neurol 54:647-654.

Monani UR, Pastore MT, Gavrilina TO, Jablonka S, Le TT, Andreassi C, DiCocco JM, Lorson C, Androphy EJ, Sendtner M, Podell M and Burghes AH (2003) "A transgene carrying an A2G missense mutation in the SMN gene modulate phenotypic severity in mice with severe (type 1) spinal muscular atrophy" J Cell Biol 160(1):41-52.