Sheffield Institute for
Translational Neuroscience

Dr Johnathan Cooper-Knock

Clinical Research Fellow

MNDA/MRC Lady Edith Wolfson Fellowship

Research Interests

My research is focused around genetic variants of motor neuron disease (MND, also called amyotrophic lateral sclerosis or ALS).  In particular I focus on the most common genetic variant associated with abnormal expansion of the gene C9ORF72.  In doing this I am pursuing a number of lines of enquiry:

  • Gene expression profiling using microarray and next generation sequencing technology. 
  • Development and application of a Southern hybridisation based technique to measure the length of the C9ORF72 expansion and explore links with clinical and molecular phenotypes.
  • Characterisation of clinical and neuropathological features of C9ORF72-MND patients.  I am attempting to identify modifiers of the disease phenotype which can be developed into therapeutic targets. 

Current Projects

I currently hold a Lady Edith Wolfson Clinical Research Training Fellowship jointly funded by the MNDA and the MRC.  The aim of this project is to characterise the function of C9ORF72 in health and disease. 

Expansions of C9ORF72 represent the most common genetic variant of motor neuron disease/ amyotrophic lateral sclerosis (MND/ALS); indeed approximately one in every ten patients carries this mutation.  This offers an opportunity the like of which has never been seen in MND/ALS research: for the first time it is possible to study a group of patients where the underlying cause of disease is known and matched; previously it is has been impossible to know whether a hypothesis was incorrect or only applicable to a limited number of patients.

I am attempting to characterise C9ORF72-MND at various levels: At the macro level including clinical and pathologically features; and at the molecular level including sizing of the C9ORF72 expansion and measurement of the effect of the expansion on the expression and splicing of the whole genome.


Cooper-Knock J, Walsh MJ, Higginbottom A, Robin Highley J, Dickman MJ, Edbauer D, Ince PG, Wharton SB, Wilson SA, Kirby J, Hautbergue GM, Shaw PJ. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain. 2014 Jul;137(Pt 7):2040-51. doi: 10.1093/brain/awu120. Epub 2014 May 27.

Hu M, Cooper J *, Beamish R, Jones E, Butterworth R, Catterall L, Ben-Shlomo Y. How well do we recognise and treat non-motor symptoms in a British Parkinson’s disease population? Journal of Neurology. 2011; 258 (8): 1513-1517

Hu M, Butterworth R, Kumar V, Cooper J *, Jones E, Catterall L, Ben-Shlomo Y. What are the determinants of sub-optimal care for Parkinson’s disease patients in the MKPD study? Parkinsonism and Related Disorders. 2011; 17(3):177-81

Cooper-Knock J, Pepper I, Hodgson T, Sharrack B.  Early diagnosis of Horner’s syndrome using topical apraclonidine. Journal of Neuro-Ophthalmology 2011 (3):214-6.

Cooper-Knock J, Ahmedzai SH, Shaw PJ.  The use of subcutaneous glycopyrrolate in management of sialorrhea in bulbar motor neuron disease and facilitating the use of non-invasive ventilation Amyotrophic Lateral Sclerosis 2011 12(6):464-5.

Goodall E, Bury J, Cooper-Knock J, Shaw PJ, Kirby J. Genetics of Familial Amyotrophic Lateral Sclerosis. Amyotrophic Lateral Sclerosis, ISBN 979-953-307-199-1 InTech 2011

Cooper-Knock J, Bury J, Ferraiuolo L, Goodall E, Shaw PJ, Kirby J. Insights Arising from Gene Expression Profiling in Amyotrophic Lateral Sclerosis. Amyotrophic Lateral Sclerosis, ISBN 979-953-307-199-1 InTech 2011

Cooper-Knock J+, Hewitt C+, Highley JR, Brockington A, Milano A, Man S, Martindale J, Hartley J , Walsh T, Gelsthorpe C, Baxter L, Forster G, Fox M, Mok K, McDermott CJ, Traynor B, Kirby J, Hardy J, Wharton SB, Ince PG, Shaw PJ. Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.

Majounie E, Renton AE, Mok K, Nicalou N, Waite A, Rollinson S, Chiò A, Restagno G, Simon-Sanchez J, van Swieten J, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R,. Orrell RW, Mead S, Houlden H,  Rohrer JD, Morrison K, Talbot K, Ansorge O, The Chromosome 9-ALS/FTD Consortium (including Cooper-Knock J), The ITALSGEN Consortium, Englund E, Borghero G, McCluskey L, Trojanowski JQ,  van Deerlin VM, Schellenberg GD, Nalls GA, Drory V, Brice A, Drepper C , Williams N, Kirby J, Shaw P, Hardy J, Singleton A, Tienari PJ, Heutink P, Morris H, Pickering-Brown A, Traynor BJ  Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11(4):323-30.

Cooper-Knock J, Kirby J, Heath P, Shaw PJ. Gene Expression Profiling in Discovery of Pathophysiology in Neurodegenerative Disease: A Review Nature Reviews Neurology 2012; 8(9):518-30

Ismail A+, Cooper-Knock J+, Highley JR, Milano A, Kirby J, Goodall E, Lowe J, Scott I, Constantinescu CS, Walters SJ, Price S, McDermott CJ, Sawcer S, Compston DAS, Sharrack B, Shaw PJ. Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72. J Neurol Neurosurg Psychiatry. 2013; 84:79-87.

Lo C, Cooper-Knock J, Garrard K, Martindale J, Williams T, Shaw P. Concurrent amyotrophic lateral sclerosis and cystic fibrosis supports common pathways of pathogenesis. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14(5-6):473-5

Buchman VL, Cooper-Knock J, Connor-Robson N, Higginbottom A, Kirby J, Razinskaya OD, Ninkina N, Shaw PJ. Simultaneous and independent detection of C9ORF72 alleles with low and high number of GGGGCC repeats using an optimised protocol of Southern blot hybridisation. Mol Neurodegener. 2013; 8:12

Jones AR, Woollacott I, Shatunov A, Cooper-Knock J, Buchman V, Sproviero W, Smith B, Scott KM, Balendra R, Abel O, McGuffin P, Ellis CM, Shaw PJ, Morrison KE, Farmer A, Lewis CM, Leigh PN, Shaw CE, Powell JF, Al-Chalabi A.. Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat.  Neurobiol Aging. 2013;34:2234.e1-7

Cooper-Knock J+, Frolov A+, Highley JR+, Charlesworth G, Kirby J, Milano A, Hartley J, Ince PG, McDermott CJ, Lashley T, Revesz T, Shaw PJ, Wood NW, Bandmann O. C9ORF72 expansions, parkinsonism and Parkinson’s Disease – a clinicopathological study. Neurology. 2013;81(9):808-11

Cooper-Knock J, Higginbottom A, Connor-Robson N, Bayatti N, Bury JJ, Kirby J, Ninkina N, Buchman VL, Shaw PJ. C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles. Neurology. 2013;81(19):1719-21.

Cooper-Knock J, Jenkins T, Shaw PJ. Clinical and Molecular Aspects of Motor Neuron Disease. Colloquium Series on Genomic and Molecular Medicine. ISBN: 9781615044283 Morgan & Claypool Life Sciences 2013.

Gallagher MD, Suh E, Grossman M, Elman L, McCluskey L, Van Swieten JC, Al-Sarraj S, Neumann M, Gelpi E, Ghetti B, Rohrer JD, Halliday G, Van Broeckhoven C, Seilhean D, Shaw PJ, Frosch MP, Alafuzoff I, Antonell A, Bogdanovic N, Brooks W, Cairns NJ, Cooper-Knock J, Cotman C, Cras P, Cruts M, De Deyn PP, Decarli C, Dobson-Stone C, Engelborghs S, Fox N, Galasko D, Gearing M, Gijselinck I, Grafman J, Hartikainen P, Hatanpaa KJ, Highley JR, Hodges J, Hulette C, Ince PG, Jin LW, Kirby J, Kofler J, Kril J, Kwok JB, Levey A, Lieberman A, Llado A, Martin JJ, Masliah E, McDermott CJ, McKee A, McLean C, Mead S, Miller CA, Miller J, Munoz DG, Murrell J, Paulson H, Piguet O, Rossor M, Sanchez-Valle R, Sano M, Schneider J, Silbert LC, Spina S, van der Zee J, Van Langenhove T, Warren J, Wharton SB, White Iii CL, Woltjer RL, Trojanowski JQ, Lee VM, Van Deerlin V, Chen-Plotkin AS. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol. 2014;127(3):407-18.

Bayatti N, Cooper-Knock J, Bury JJ, Wyles M, Heath PR, Kirby J, Shaw PJ. Comparison of blood RNA extraction methods used for gene expression profiling in amyotrophic lateral sclerosis. PLoS One. 2014;9(1):e87508.

Cooper-Knock J, Shaw PJ, Kirby J. The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype. Acta Neuropathol. 2014;127(3):333-45. 

* Surname altered from Cooper to Cooper-Knock following marriage in December 2008.

+ Equal contribution to authorship

Professional Activities

Peer review of grant applications for funding bodies including ALS Society of Canada and the Garfield Weston Foundation.

Peer review of submitted articles for journals including the Journal of Neurology, Neurosurgery and Psychiatry and the European Journal of Neurology.


I studied medicine at the University of Oxford where I obtained a 1st Class Honours degree in Physiological Sciences and my degree in Clinical Medicine; I graduated in 2006.  During my degree I completed a research project under the supervision of Professor Kevin Talbot investigating clinical subtypes of MND.

In 2008 I was awarded a NIHR Academic Clinical Fellowship in Sheffield under the supervision of Professor Pamela Shaw.  While continuing my clinical training and completing my MRCP I started my research training in the lab which I continued in 2010 as a Peake Start-Up Fellowship.  This allowed me to obtain the pilot data for an application to the MNDA/MRC in 2012 when I was awarded a Lady Edith Wolfson Clinical Research Training Fellowship to allow me to complete my PhD; I am due to complete my studies in 2015. 


2012 European Network for Cure of ALS (ENCALS) Research Presentation Prize

2012 North of England Neurological Association (NENA) Liversedge Prize for Best Research Presentation

Contact Details

Academic Neurology Unit
Department of Neuroscience
Sheffield Institute for Translational Neuroscience
University of Sheffield
Room B24
385a Glossop Road
S10 2HQ

T: +44 (0)114 2222273