Dr. Russell Mc Laughlin

Summary

Amyotrophic 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 Agency

Science Foundation Ireland

Programme

Career Development Award

Summary

Most 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 Agency

SFI FutureNeuro Research Centre

Programme

Research Centres

Summary

One 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 Agency

MND Association (UK)

Programme

Junior non-clinical fellowship

Summary

This novel project will examine the entire genetic code of over 1,000 Irish people, along with 21,000 samples from other countries, to identify the genetic basis of Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. Changes in the genetic code of people affected with ALS contribute to the risk of disease, but the absence of knowledge of how genomics influence the way the disease manifests represents the largest obstacle to developing effective treatments. The project will examine the interplay between ancestral origin and the development of disease in Irish patients, leading to precision based treatments in collaboration with industry partners.

Funding Agency

Science Foundation Ireland

Programme

Strategic Partnership Programme

Project Type

Research Project

Summary

Funding Agency

Wellcome Trust

Programme

Trinity College Dublin Institutional Strategic Support Fund