Dr. Russell Mc Laughlin
Associate Professor, Genetics
Email russell.mclaughlin@tcd.ie Phone3531896 1288bioinf.gen.tcd.ie/ctgPublications and Further Research Outputs
- Kleinerova J, Tahedl M, Tan EL, Delaney S, Hengeveld JC, Doherty MA, McLaughlin RL, Hardiman O, Chang KM, Finegan E, Bede P., Supra- and infra-tentorial degeneration patterns in primary lateral sclerosis: a multimodal longitudinal neuroradiology study., J Neurol., 2024Journal Article, 2024
- Opie-Martin, S. and Iacoangeli, A. and Topp, S.D. and Abel, O. and Mayl, K. and Mehta, P.R. and Shatunov, A. and Fogh, I. and Bowles, H. and Limbachiya, N. and Spargo, T.P. and Al-Khleifat, A. and Williams, K.L. and Jockel-Balsarotti, J. and Bali, T. and Self, W. and Henden, L. and Nicholson, G.A. and Ticozzi, N. and McKenna-Yasek, D. and Tang, L. and Shaw, P.J. and Chio, A. and Ludolph, A. and Weishaupt, J.H. and Landers, J.E. and Glass, J.D. and Mora, J.S. and Robberecht, W. and Damme, P.V. and McLaughlin, R. and Hardiman, O. and van den Berg, L. and Veldink, J.H. and Corcia, P. and Stevic, Z. and Siddique, N. and Silani, V. and Blair, I.P. and Fan, D.-S. and Esselin, F. and de la Cruz, E. and Camu, W. and Basak, N.A. and Siddique, T. and Miller, T. and Brown, R.H. and Al-Chalabi, A. and Shaw, C.E., Correction to: The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration (Nature Communications, (2022), 13, 1, (6901), 10.1038/s41467-022-34620-y), Nature Communications, 15, (1), 2024Journal Article, 2024, DOI , URL
- Bagnasco, G. and Marzullo, M. and Cattaneo, C. and Biehler-Gomez, L. and Mazzarelli, D. and Ricciardi, V. and MÃŒller, W. and Coppa, A. and McLaughlin, R. and Motta, L. and Prato, O. and Schmidt, F. and Gaveriaux, F. and Marras, G.B. and Millet, M.A. and Madgwick, R. and Ballantyne, R. and Makarewicz, C.A. and Trentacoste, A. and Reimer, P. and Mattiangeli, V. and Bradley, D.G. and Malone, C. and Esposito, C. and Breslin, E.M. and Stoddart, S., Bioarchaeology aids the cultural understanding of six characters in search of their agency (Tarquinia, ninthâ"seventh century BC, central Italy), Scientific Reports, 14, (1), 2024Journal Article, 2024, DOI , URL
Research Expertise
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TitleDetecting the dark matter of neurodegeneration: repeat expansions in amyotrophic lateral sclerosisSummaryAmyotrophic lateral sclerosis (ALS) is an incurable, rapidly fatal neurodegenerative disease characterised by loss of upper and lower motor neurones (the nerve cells that control movement) resulting in progressive paralysis and death from respiratory failure. Although it is clear that genetic risk factors play a role in the underlying causes of the disease, currently only around 10-15% of ALS cases can be explained by established causative genes. For effective treatments to be developed in ALS, there is urgent need to understand its central pathophysiology. This begins with establishing all of the underlying genetic causes of ALS. The most significant causative gene identified in ALS to date is C9orf72. In this gene, an unconventional genetic mutation known as a repeat expansion (RE) initiates a cellular process called RAN translation, leading to toxic accumulation of junk protein and subsequent neurodegeneration. Although this is currently poorly understood, several lines of evidence strongly implicate RAN translation as a central disease process in ALS and REs may therefore be the most important class of mutation in the disease. However, this hypothesis has remained unexplored due to technological constraints; REs have traditionally been extremely difficult to discover using established techniques. Exploiting recent advances in genomic science and technology that address many of the limitations of previous methods, this study will apply a suite of emerging methodologies to discover novel REs in ALS to elucidate the central disease mechanisms underlying neurodegeneration. The project will follow three principal strands. The first uses data generated in Project MinE, a consortium-based ALS genome sequencing project currently underway in the applicant's laboratory (in collaboration with Professor Orla Hardiman) which is generating short-read whole-genome sequencing data for 700 Irish ALS individuals and 350 control subjects. Using a novel software method developed by the Applicant that can identify the locations of likely REs (and accurately predict C9orf72 mutation status), the locations of novel REs elsewhere in the genome will be pinpointed and examined using wet-lab validation techniques to verify their involvement in ALS. The second approach will be to characterise REs known to cause other neurodegenerative diseases such as spinocerebellar ataxias (SCAs) in ALS cases. Although most of these genes have not been extensively studied in ALS, such an investigation is justified, as intermediate-length REs in the SCA2 gene ATXN2 are known to be associated with ALS, thus providing rationale to explore other SCA genes in ALS. The final method will be to use cutting-edge third-generation sequencing technologies (eg Oxford Nanopore), which sequence very long DNA molecules, to identify novel REs in ALS. This represents the state-of-the-art in genome sequencing technology and is a rapidly evolving field. This strand of the project would be an early and ground-breaking adoption of such technology for the exploration of the genetic causes of neurodegeneration.Funding AgencyScience Foundation IrelandDate From2018-01-01Date To2021-12-31
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TitleThe genetic pleiotropy of neurodegenerative mutationsSummaryMost neurological diseases have complex genetic origins, involving contributions from common and rare genetic variants via mono-, oligo- and polygenic mechanisms. Over the past decade, our understanding of these genetic origins has steadily improved through mega-scale genome-wide association studies (GWAS) and whole-genome/whole-exome sequencing (WGS/WES) projects, yielding an increasingly clear blueprint of the genetic architectures of these conditions and heralding fresh biological understanding and potential therapeutic avenues. These genetic insights have also revealed hitherto unrecognised relationships between clinically disparate conditions, including our biologically intriguing observation of genetic correlation between the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and schizophrenia2. Much remains to be discovered in the genetic mechanisms underpinning most neurological diseases; to this end, this genetic pleiotropy - multiple traits resulting from the same genetic variant(s) - can be harnessed to fast-track the discovery of novel genetic mechanisms by leveraging established knowledge from one trait in another. The proposed project will leverage expertise in Dr McLaughlin's group to investigate the role of established causes of neurodegeneration in a range of neurological diseases. Current work in Dr McLaughlin's laboratory is delineating the contribution of a unique type of genetic variant called a repeat expansion to ALS pathogenesis; the proposed work will exploit techniques developed in this work to expand the diseases of interest to epilepsies and encephalopathies. Dr McLaughlin has generated WGS data for over 700 Irish ALS cases and controls; this will be supplemented with WGS data for up to 50-100 encephalopathy parent-offspring trios (in collaboration with FutureNeuro PI Gianpiero Cavalleri) for the discovery of potential novel disease-causing repeat expansions. In addition, we will also explore the role of established repeat expansions (including the ALS-causing C9orf72) in up to 2,000 epilepsy patients, following a recent report of the involvement of this gene in teenage-onset progressive myoclonic epilepsy6. Dr McLaughlin's Irish control WGS data will be used as a healthy control cohort and, where possible (for repeat expansions within exons), results will be validated using 25,000 exomes from the Epi25 Consortium project through research agreements in place with Prof. Cavalleri.Funding AgencySFI FutureNeuro Research CentreDate From2020-01-01Date To2021-12-31
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TitleWhole-genome sequencing of 1000 Irish ALS patients and controls to identify novel ALS genes and pathwaysSummaryOne of the main obstacles to the development of effective treatments for ALS, the most common form of motor neurone disease, is our incomplete understanding of its underlying causes. Many lines of evidence indicate that a substantial proportion of the causes stem from differences in the genetic code of ALS patients, yet only a small number of these differences - called mutations - have been identified. This project will examine, in exquisite detail, the entire genetic code (the genomes) of over 1,000 Irish individuals, 700 of whom have ALS, to identify mutations that cause the disease. By examining ALS patients' genomes in the relatively small Irish population we can reconstruct large family trees for ALS patients who were previously assumed to be unrelated. This makes possible the task of distinguishing disease-causing mutations from benign genetic variation. Examination of 1,000 Irish genomes will also allow us to investigate the effect of ancestry on risk of developing ALS. Are people of mixed ancestry (eg half English/half Irish, or Anglo-Saxon ancestry vs Celtic ancestry) less likely to develop ALS? Is the lower risk of ALS that we have observed in particular regions of Ireland a consequence of the ancestry of the individuals living there or is it a local environmental effect? With the data generated in this study, we will be able to answer these questions and shed light on the question of genetic vs environmental risk factors for developing ALS. Overall, our research will help to clarify the underlying biology of ALS and open new avenues of research for understanding the disease, developing effective therapies and improving diagnosis and management of motor neurone disease.Funding AgencyMND Association (UK)Date From01/01/2016Date To31/12/2018
Recognition
- European Network to Cure ALS Young Investigator Award 2018
- Irish Laboratory Awards Young Leader of the Year 2018
- Best presentation award, 4th Frontiers in Neurology conference 2014