Sheffield Institute for
Translational Neuroscience

Dr Johnathan Cooper-Knock

NIHR Clinical Lecturer

Research Interests

Genetic causes of motor neuron disease (MND, also called amyotrophic lateral sclerosis or ALS).  In particular the discovery of novel genetic mutations to facilitate the design of cell and animal models for identification of new potential therapeutic targets.

Current Projects

Amyotrophic lateral sclerosis (ALS, also called motor neuron disease) is a fatal and aggressive disease without an effective treatment.  In recent times the discovery of genetic causes of disease has highlighted certain biological functions, which has allowed development of novel therapeutic approaches.  A number of these therapies are effective in animal models and are on their way to the clinic. The drawback with these approaches to date is that they are only relevant to a small proportion of ALS patients who have disease caused by a particular genetic mutation.  This should not be the case - studies have suggested that as much as 70% of ALS may be caused by one or more genetic variations acting in concert, even in sporadic ALS patients who do not have a family history of disease. One of the reasons for missing heritability is that the majority of the genome, which does not directly encode protein sequence, is relatively poorly studied.  

Dr Cooper-Knock is working to uncover the basis for that missing heritability.

To do so, he is combining established and cutting-edge bioinformatics techniques together with the largest ever disease-specific whole genome sequencing effort (22000 genomes) to identify non-coding changes which cause and modify ALS.  

This work builds on Dr Cooper-Knock’s PhD work - focusing on C9orf72-ALS  - and his recent discovery of novel disease-causing mutations within RNA-binding proteins (Cooper-Knock et al 2017).

Dr Cooper-Knock is a Clinical Lecturer, funded by NIHR. He has also received grants from the Academy of Medical Sciences, the Medical Research Council (MRC), and the Motor Neurone Disease Association (MNDA).

Research Team

  • Tobias Moll (PhD Student)
  • Ian Fox (MSc Student)


Cooper-Knock J, Robins H, Niedermoser I, Wyles M, Heath PR, Higginbottom A, Walsh T, Kazoka M, Project MinE ALS Sequencing Consortium, Ince PG, Hautbergue GM, McDermott CJ, Kirby J, Shaw PJ.   Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype. Frontiers in Molecular Neuroscience. 2017 10:370

Waller R, Goodall EF, Milo M, Cooper-Knock J, Da Costa M, Hobson E, Kazoka M, Wollff H, Heath PR, Shaw PJ, Kirby J. Serum miRNAs miR-206, 143-3p and 374b-5p as potential biomarkers for amyotrophic lateral sclerosis (ALS). Neurobiology of Aging 2017 55:123-131

Hautbergue GM, Castelli LM, Ferraiuolo L, Sanchez-Martinez A, Cooper-Knock J, Higginbottom A, Lin YH, Bauer CS, Dodd JE, Myszczynska MA, Alam SM, Garneret P, Chandran JS, Karyka E, Stopford MJ, Smith EF, Kirby J, Meyer K, Kaspar BK, Isaacs AM, El-Khamisy SF, De Vos KJ, Ning K, Azzouz M, Whitworth AJ, Shaw PJ.  SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nature Communications 2017 8:16063

Nithiananthan S, Crawford A, Cooper-Knock J, Lambert DW, Whawell SA.  Physiological Fluid Flow Moderates Fibroblast Responses to TGF‐β1. Journal of Cellular Biochemistry. 2017 118:878-890

Cooper-Knock J, Green C, Altschuler G, Wei W, Bury JJ, Heath PR, Wyles M, Gelsthorpe C, Highley JR, Lorente-Pons A, Beck T, Doyle K, Otero K, Traynor BJ, Kirby J, Shaw PJ, Hide W. A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis. Acta Neuropathologica Communications. 2017 5:23

Stopford MJ, Higginbottom A, Hautbergue GM, Cooper-Knock J, Mulcahy PJ, De Vos KJ, Renton AE, Pliner H, Calvo A, Chio A, Traynor BJ, Azzouz M, Heath PR, ITALSGEN Consortium, NeuroX Consortium, Kirby J, Shaw PJ. C9ORF72 hexanucleotide repeat exerts toxicity in a stable, inducible motor neuronal cell model, which is rescued by partial depletion of Pten. Human Molecular Genetics 2017 26:1133-1145

Beer AM, Cooper-Knock J, Fletcher S, Brown-Wright SH, Nandakumar TP, Shaw PJ.  Case report of concurrent Fabry disease and amyotrophic lateral sclerosis supports a common pathway of pathogenesis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2016 17:614-616

Bury JJ, Highley JR, Cooper-Knock J, Goodall EF, Higginbottom A, McDermott CJ, Ince PG, Shaw PJ, Kirby J.  Oligogenic inheritance of optineurin (OPTN) and C9ORF72 mutations in ALS highlights localisation of OPTN in the TDP-43-negative inclusions of C9ORF72-ALS. Neuropathology. 2016 36:125-134

Highley JR, Lorente Pons A, Cooper-Knock J, Wharton SB, Ince PG, Shaw PJ, Wood J, Kirby J. Motor neurone disease/amyotrophic lateral sclerosis associated with intermediate-length CAG repeat expansions in Ataxin-2 does not have 1C2-positive polyglutamine inclusions. Neuropathol Appl Neurobiol. 2016 42:377-389

Abramycheva NY, Lysogorskaia EV, Stepanova MS, Zakharova MN, Kovrazhkina EA, Razinskaya OD, Smirnov AP, Maltsev AV, Ustyugov AA, Kukharsky MS, Khritankova IV, Bachurin SO, Cooper-Knock J, Buchman VL, Illarioshkin SN, Skvortsova VI, Ninkina N. C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population. Neurobiol Aging. 2015 36:2908.e5-9.

Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, Kirby J, Hautbergue GM and Shaw PJ. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy Acta Neuropathologica 2015 130:63-75

Cooper-Knock J, Bury JJ, Heath PR, Wyles M, Higginbottom A, Walsh MJ, Gelsthorpe C, Highley JR, Hautbergue GM, Rattray M, Kirby J, Shaw PJ. C9ORF72 GGGGCC expanded repeats produce splicing dysregulation which correlates with disease severity in amyotrophic lateral sclerosis. PLoS One 2015 10:e0127376

Beer AM, Cooper-Knock J, Higginbottom A, Highley JR, Wharton SB, Ince PG, Milano A, Jones AA, Al-Chalabi A, Kirby J, Shaw PJ. Intermediate length C9orf72 expansion in an ALS patient without classical C9orf72 neuropathology. Amyotroph Lateral Scler Frontotemporal Degener. 2015 16:249-251

Cooper-Knock J*, Kirby J*, Highley JR and Shaw PJ. The spectrum of C9orf72 mediated neurodegeneration and amyotrophic lateral sclerosis (ALS). Neurotherapeutics. 2015 12:326-339

Walsh MJ*, Cooper‐Knock J*, Dodd JE, Stopford MJ, Mihaylov SR, Kirby J, Shaw PJ, Hautbergue GM. Decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Neuropathology and Applied Neurobiology. 2015 41:109-134

Peters OM, Shelkovnikova T, Highley JR, Cooper‐Knock J, Hortobágyi T, Troakes C, Natalia Ninkina N, Buchman VL. Gamma‐synuclein pathology in amyotrophic lateral sclerosis. Annals of Clinical and Translational Neurology. 2015 2:29-37

Highley JR, Kirby J, Jansweijer JA, Webb PS, Hewamadduma CA, Heath PR, Higginbottom A, Raman R, Ferraiuolo L, Cooper-Knock J, McDermott CJ, Wharton SB, Shaw PJ, Ince PG. Loss of nuclear TDP-43 in ALS causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurons. Neuropathology and Applied Neurobiology. 2014 40:670-85

Green NH, Nicholls Z, Heath PR, Cooper-Knock J, Corfe BM, MacNeil S, Bury JP. Pulsatile exposure to simulated reflux leads to changes in gene expression in a 3D model of oesophageal mucosa. International Journal of Experimental Pathology. 2014 95:216-28

Cooper-Knock J*, Walsh MJ*, Higginbottom A, Highley JR, 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; 137:2040-51

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;127:333-45.

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;127:407-18.

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:e87508.

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. Molecular Neurodegeneration. 2013; 8:1-6

Cooper-Knock, J., A. Higginbottom, N. Connor-Robson, N. Bayatti, J. J. Bury, J. Kirby, et al. C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles. Neurology 2013; 81:1719-21

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.

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 ALS-causing hexanucleotide repeat. Neurobiology of Aging 34:2234

Lo C, Cooper-Knock J, Garrard K, Martindale J, Williams T, Shaw PJ. Concurrent amyotrophic lateral sclerosis and cystic fibrosis supports common pathways of pathogenesis. Amyotroph Lateral Scler Frontotemporal Degener. 2013; 14:473-475

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 disease: a clinicopathologic study. Neurology 2013; 81: 808-8114

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

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; 8:518-30

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 PJ, 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;11:323-30.

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;135:751-64.

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, 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 12:464-5.

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

Tate M, Cooper-Knock J, Hunter Z, Wood E, Pearson, Blackburn DJ. Neurology and Clinical Neuroanatomy: on the move CRC Press 2015

Hu M, Butterworth R, Kumar V, Cooper J#, Jones E, Catterall L, Ben-Shlomo Y. How common and what are the determinants of sub-optimal care for Parkinson's disease patients: the Milton Keynes community study. Parkinsonism and Related Disorders 2011 17:177-81

Hu M, Cooper J#, Beamish R, Jones E, Butterworth R, Catterall L, Ben-Shlomo Y. How well do we recognise non-motor symptoms in a British Parkinson's disease population? J Neurol 2011 258:1513-7

# 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, the Garfield Weston Foundation and the MNDA (UK).

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

Regular contributor to ‘Alzforum’ website ( – a resource dedicated to helping researchers accelerate discovery in Alzheimer’s disease and related disorders.

Regular platform presentations of research at international meetings including the last five ALS/MND International Symposia in Brussels, Orlando, Dublin, Boston and Milan.


Johnathan Cooper-Knock studied medicine at the University of Oxford where he obtained a 1st Class Honours degree in Physiological Sciences and completed a degree in Clinical Medicine graduating in 2006.  During his undergraduate studies Johnathan completed a research project under the supervision of Professor Kevin Talbot investigating clinical subtypes of MND.

In 2008 Johnathan was awarded a NIHR Academic Clinical Fellowship in Sheffield under the supervision of Professor Pamela Shaw.  He continued research initially as a Peake Start-Up fellow before being awarded a Lady Edith Wolfson Clinical Research Training Fellowship funded by the MNDA/MRC which facilitated the award of a PhD by publication in 2015.

During Johnathan’s PhD he focused on characterisation of a novel genetic variant.  More recently he has gained proficiency in genetics and is now leading investigation of the non-coding genome in the largest ever disease-specific whole genome sequencing project which is focused on ALS (  In 2017 Johnathan was awarded the European Network for Cure of ALS (ENCALS) Young Investigator Award.  


2017 European Network for Cure of ALS (ENCALS) Young Investigator Award

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

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

Teaching Interests

Neurodegenerative disease

PhD Supervision

2017-present Tobias Moll Characterisation of a novel genetic variant of amyotrophic lateral sclerosis’

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