Institute for Neuroscience and Muscle Research

Lab head: A/Prof Sandra Cooper
Location: Kids Research Institute, The Children's Hospital at Westmead

The INMR studies the causes, consequences and therapies for patients with inherited neuromuscular disorders. Neuromuscular disorders encompass a large group of inherited disorders that cause abnormalities in the structure and function of our skeletal muscle or nerves. These disorders can have devastating consequences for affected children, often resulting in the loss of the ability to walk or perform activities of daily living, and many are life-limiting. 

Our research programs ranges from Gene Discovery using latest technologies in next generation sequencing to identify new causes of inherited muscle and nerve disorders, fundamental neurochemistry trying to unlock the mechanism underlying disease, through to clinical trials to evaluate new therapies for our patients.

Lab members: Membrane Repair Team - Frances Lemckert, Postdoc - Tatiana Benavides, Postdoc - Ann-Katrin Piper, PhD student - Natalie Woolger, PhD student - Adam Bournazos, RA - Reece Sophocleous, RA Gene Discovery Team - Emily Oates, Geneticist and NHMRC Fellow - Sarah Sandaradura, Geneticist/PhD student - Gina O¿Grady, Neurologist/PhD student - Roula Ghaoui, Neurologist/PhD student - Leigh Waddell, Postdoc - Michaela Yuen, Postdoc - Heather Best, PhD student
Funding: NHMRC, Brain Foundation, Jain Foundation
Research approach equipment: Next Generation Sequencing and Bioinformatics Cellular neurochemistry - including culturing muscle cells from human patients and controls Protein trafficking and localisation Cutting edge fixed and live cell microscopy imaging CRISPR Gene editing Animal models of human disease

Lisa Riley, Sandra Cooper, Peter Hickey, Joëlle Rudinger-Thirion, Mathew McKenzie, Alison Compton, Sze Chern Lim, David Thorburn, Michael Ryan, Richard Giegé, Melanie Bahlo, John Christodoulou (2010). A Mitochondrial Tyrosyl-tRNA Synthetase (YARS2) Mutation is a Novel Cause of Myopathy, Lactic Acidosis and Sideroblastic Anaemia (MLASA). Am J Hum Genet.2010 Jul 9;87(1):52-9.(IF 11.3)

 Angela Lek, Monkol Lek, Kathryn N. North, Sandra T. Cooper. Phylogenetic analysis of ferlin genes reveals ancient eukaryotic origins. BMC Evolutionary Biology 2010; 29(10):231.(IF 4.3)

Evesson FJ, Peat RA, Lek A, Brilot F, Lo HP, Dale RC, Parton RG, North KN, Cooper ST. Reduced plasma membrane expression of dysferlin mutants is due to accelerated endocytosis via a syntaxin-4 associated pathway. J Biological Chemistry 2010;285(37):28529-39. (IF5.9).

Importance and challenge of making an early diagnosis in LMNA-related muscular dystrophy. Menezes MP, Waddell LB, Evesson FJ, Cooper S, Webster R, Jones K, Mowat D, Kiernan MC, Johnston HM, Corbett A, Harbord M, North KN, Clarke NF. Neurology 2010; 17;78(16):1258-63. (IF 8.2).

Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch. Waddell LB, Lemckert FA, Zheng XF, Tran J, Evesson FJ, Hawkes JM, Lek A, Street NE, Lin P, Clarke NF, Landstrom AP, Ackerman MJ, Weisleder N, Ma J, North KN, Cooper ST. J Neuropathol Exp Neurology 2011; 70(4):302-13. (IF 5.1).

Ferlins: regulators of vesicle fusion for auditory neurotransmission, receptor trafficking and membrane repair. Lek A, Evesson FJ, Sutton RB, North KN, CooperST. Traffic 2012 Feb;13(2):185-94. (IF 5.1)

Angela Lek, Frances J. Evesson, Frances A. Lemckert, Gregory M.I. Redpath, Lynne Turnbull, Cynthia B. Whitchurch, Kathryn N. North and Sandra T. Cooper. Calpains, cleaved mini-dysferlinC72 and L-type channels underpin calcium-dependent muscle membrane repair. J Neuroscience 2013, 33(12):5085–5094(IF 7.1).

Gaignard P, Menezes M, Schiff M, Bayot A, Rak M, Ogier de Baulny H, Su CH, Gilleron M, Lombes A, Abida H, Tzagoloff A, Riley L, Cooper ST, Mina K, Sivadorai P, Davis MR, Allcock RJ, Kresoje N, Laing NG, Thorburn DR, Slama A, Christodoulou J, Rustin P. Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia. Am J Hum Genet. 2013Aug 8;93(2):384-9. (IF 11.4)

Riley LG, Menezes MJ, Rudinger-Thirion J, Duff R, de Lonlay P, Rotig A, Tchan MC, Davis M, CooperST, Christodoulou J. Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia. Orphanet J Rare Dis. 2013 Dec 17;8:193-9. (4.3)

Fuson K, Rice A, Mahling R, Snow A, Nayak K, Shanbhogue P, Meyer AG, Redpath GM, Hinderliter A, CooperST, Sutton RB. Alternate Splicing of Dysferlin C2A Confers Ca(2+)-Dependent and Ca(2+)-Independent Binding for Membrane Repair. Structure 2014 Jan 7;22(1):104-15. (IF 6.4)

Redpath, GMI, Woolger, N, Piper, AK, Lemckert, FA, Lek, A, Greer, PA, North, KN, Cooper, ST. Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair. Molecular Biology of the Cell 2014.2014 Oct 1;25(19):3037-48 (IF 6.2).

Menezes MJ, Guo Y, Zhang J, Riley LG, Cooper ST, Thorburn DR, Li J, Dong D, Li Z, Glessner J, Davis RL, Sue CM, Alexander SI, Arbuckle S, Kirwan P, Keating BJ, Xu X, Hakonarson H, Christodoulou J. Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Hum Mol Genet. 2015 Apr 15;24(8):2297-307.  (IF 6.4).

Sztal TE, Zhao M, Williams C, Oorschot V, Parslow AC, Giousoh A, Yuen M, Hall TE, Costin A, Ramm G, Bird PI, Busch-Nentwich EM, Stemple DL, Currie PD, Cooper ST, Laing NG, Nowak KJ, Bryson-Richardson RJ. Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function. Acta Neuropathol. 2015 Sep;130(3):389-406. (IF 10.7)

Ghaoui R, Cooper ST, Lek M, Jones K, Corbett A, Reddel SW, Needham M, Liang C, Waddell LB, Nicholson G, O'Grady G, Kaur S, Ong R, Davis M, Sue CM, Laing NG, North KN, MacArthur DG, Clarke NF. Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned. JAMA Neurol. 2015 Oct 5:1-9. doi: 10.1001/jamaneurol.2015.2274. [Epub ahead of print] (IF 7.4)

Yuen M, Cooper ST, Marston SB, Nowak KJ, McNamara E, Mokbel N, Ilkovski B, Ravenscroft G, Rendu J, de Winter JM, Klinge L, Beggs AH, North KN, Ottenheijm CA, Clarke NF. Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres. Hum Mol Genet. 2015 Aug 24. pii: ddv334. [Epub ahead of print] (IF 6.4)

To study disease mechanism a new form of myopathy using CRISPR/Cas9-mediated fluorescent labelling, live-cell microscopy and protein-interaction studies.

Primary supervisor: Sandra Cooper

As part of our large program in translational genomics, we have identified a new gene that causes an early–onset myopathy in children. The gene is an oxidoreductase, and is previously unstudied in the published literature. It is rare to find something utterly uncharacterised in 2016, and this gene is essential for life.  This gene introduces altered redox as a new pathway in the myopathies, with many similarities to features of neurodegenerative disorders. We want to study how this protein responds to oxidative stress, and find which substrates it regulates the redox state of that cells cannot live without.

Discipline: Applied Medical Sciences, Westmead
Co-supervisors: Frances Lemckert, Frances Evesson
Keywords: Animal Models of disease, Cell biology, Neurosciences, Muscular dystrophy