Meet the team

Marc-David Ruepp

"We aim to elucidate the physiological functions of FUS, as well as the pathomechanisms leading to FUS-linked Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. With these complementary approaches we are working towards closing the knowledge gap, to allow for the identification of urgently needed therapeutic approaches to prevent or alleviate neurodegeneration." Marc-David Ruepp
UK DRI Group Leader

With expertise in RNA and CRISPR, Dr Marc-David Ruepp joins the UK DRI at Kings to lead a new research group. Obtaining his PhD from the University of Bern, Switzerland, in 2009, he went on to complete postdoctoral training in Oliver Mühlemann’s lab, followed by establishing his first group in 2015. Marc-David is academic editor at Cell Stress, and received the title of 'Privatdozent' in 2018. At the UK DRI his lab will focus on the role of RNA-binding proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

1. At a glance

Understanding the role of RNA in neurodegeneration

Almost three decades ago, loss of function mutations in the RNA-binding proteins SMN were identified to be causative for Spinal Muscular Atrophy (SMA) and altered RNA metabolism emerged as potential key player in neurological disorders. Further evidence for its involvement in these diseases has come from the identification of the DNA/RNA-binding protein TDP-43 as a major protein component in the pathologic inclusions in most patients with sporadic Amyotrophic Lateral Sclerosis (ALS) and the most common form of frontotemporal lobar degeneration (FTLD-TDP). Subsequently, the identification of ALS/FTD spectrum disease-causing mutations in other RNA-binding proteins (including FUS) reinforced the link between altered RNA metabolism and neurodegeneration. The importance of RNA metabolism for neuronal homeostasis is further implicated by the fact that cytoplasmic inclusions of the RNA binding proteins TDP-43 and FUS are present in approximately 98% of all ALS and 54% of all FTD cases.

RNA is an important molecule in the cell, serving many functions which include providing the link between DNA and the proteins that it codes. However, there is emerging evidence that problems with RNA function are connected with different neurodegenerative diseases and may be a causative agent.

For example, at least 85 mutations in the FUS gene, which codes for an RNA-binding protein, cause amyotrophic lateral sclerosis (ALS), a devastating progressive neurodegenerative disease characterised by loss of motor neuron function. People with ALS caused by faults in the FUS gene tend to develop the disease at a younger age, with rapid progression – and some will also develop frontotemporal dementia (FTD) which affects a person’s behaviour, personality and language abilities.

The FUS gene encodes a protein that has several key functions inside our cells, many of which involve binding with RNA. In people with FUS-linked ALS and FTD, the FUS protein and RNA get trapped in the wrong location inside neurons forming clumps (aggregates). This is thought to underpin cell death.

Dr Marc-David Ruepp is aiming to understand the normal functions of FUS to gain new insight into the molecular mechanisms leading to FUS-linked ALS and FTD. This knowledge will lay the foundations for future development of effective therapies to prevent or alleviate neurodegeneration in different diseases.

2. Scientific goals

Almost three decades ago, loss of function mutations in the RNA-binding proteins SMN were identified to be causative for Spinal Muscular Atrophy (SMA) and altered RNA metabolism emerged as potential key player in neurological disorders. Further evidence for its involvement in these diseases has come from the identification of the DNA/RNA-binding protein TDP-43 as a major protein component in the pathologic inclusions in most patients with sporadic Amyotrophic Lateral Sclerosis (ALS) and the most common form of frontotemporal lobar degeneration (FTLD-TDP). Subsequently, the identification of ALS/FTD spectrum disease-causing mutations in other RNA-binding proteins (including FUS) reinforced the link between altered RNA metabolism and neurodegeneration. The importance of RNA metabolism for neuronal homeostasis is further implicated by the fact that cytoplasmic inclusions of the RNA binding proteins TDP-43 and FUS are present in approximately 98% of all ALS and 54% of all FTD cases.

FUS-linked ALS and FTD are relatively rare and account for approximately 4 to 5% of familial ALS (and some sporadic ALS cases), and about 10% of all FTD cases. However, de-novo FUS mutations are the most frequent genetic cause in early-onset ALS patients. Patients with strong cytoplasmic mislocalisation of ALS-FUS show early disease onset and aggressive progression compared to other ALS cases. Early onset and rapid disease progression are also observed in FUS-linked FTLD. This aggressive disease profile implies that either different disease mechanisms apply to FUS-linked ALS/FTD or that hastened disease onset is due to drastic pathological alterations.

FUS functions in several processes required for proper gene expression, such as transcription, pre-mRNA splicing, and miRNA processing. However, its precise role in these processes and most of its targeted RNAs are, as yet, unknown. This UK DRI programme, led by Dr Marc-David Ruepp, combines in vivo disease modelling in mice with in vitro disease modelling in human isogenic induced pluripotent stem cell (iPSC) models. It aims to uncover the molecular mechanisms responsible for neurodegeneration, and works towards elucidating the physiological function of FUS - understanding these molecular mechanisms will serve as the basis for future development of effective therapies. The results are expected to not only reveal the molecular mechanism leading to FUS-associated ALS and FTLD but more generally to provide significant new insight into the emerging connection between misregulation of RNA metabolism and neurodegeneration.

Main objectives and research goals:

1. To elucidate the physiological functions of FUS. Using in vivo and in vitro approaches to elucidate the mechanism of FUS homeostasis as well as its impact towards the development of ALS and FTLD. 

2. To directly elucidate the pathomechanisms of ALS-linked mutations across genes and across neurodegenerative diseases. Investigations of the pathomechanisms of ALS in isogenic motor neurons across ALS-linked genes and mutations and other neurodegenerative diseases.

3. Team members

Dr Anny Devoy (Postdoctoral Research Fellow)
Daniel Jutzi (PhD Student)
Jonas Mechtersheimer (PhD Student)
Angela Perry (PhD student)
Lawrence Garrett (Technician)

4. Collaborations

Within UK DRI:

  • Prof Chris Shaw, UK DRI at Kings
  • Prof Annalisa Pastore, UK DRI at Kings
  • Dr Sarah Mizielinska, UK DRI at Kings

Beyond UK DRI:

  • Dr Sandrine Thuret, King's College London
  • Dr Caroline Vance, King's College London
  • Prof Helene Plun-Favreau, UCL
  • Prof Frédéric Allain, ETH Zurich
  • Prof Mihaela Zavolan, University of Basel
  • Dr Dorothee Dormann, Ludwig-Maximilians-University Munich
  • Prof Silvia Barabino, University of Milano-Bicocca
  • Prof Oliver Mühlemann, University of Bern

5. Topics

FUS, amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD), RNA metabolism, iPSC disease models

6. Techniques

CLIP, iPSC cell culture, CRISPR-Trap, RNA-sequencing, qRT-PCR, MST, Affinity and Immunoprecipitation from cell extracts

7. Key publications

Plewka, P., Szczesniak, M., Stepien, A., Zywicki, M., Pacak, A., Colombo, C., Makalowska, I., Ruepp, M.-D., Raczynska, D. FUS controls the processing of snoRNAs into smaller RNA fragments that can regulate gene expression. BioRxiv; 2018 (preprint) doi: https://doi.org/10.1101/409250

Loughlin, F. E., Lukavsky, P. J., Kazeeva, T., Reber, S., Hock, E-M., Colombo, M., Von Schroetter, C., Pauli, P., Cléry, A., Mühlemann, O., Polymenidou, M., Ruepp, M-D. & Allain, F. H-T. The Solution Structure of FUS Bound to RNA Reveals a Bipartite Mode of RNA Recognition with Both Sequence and Shape Specificity. Molecular Cell 2019; 73, 3, p. 490-504.e6

Jutzi, D., Akinyi, M.V., Mechterheimer, J., Frilander, M. J., Ruepp, M.-D. The emerging role of minor intron splicing in neurological diseases. Cell Stress 2018; 2(3):40-54.

Reber, S., Mechtersheimer, J., Nasif, S., Benitez, J.A., Colombo, M., Domanski, M., Jutzi, D., Hedlund, E. and Ruepp, M.D., 2018. CRISPR-Trap: a clean approach for the generation of gene knockouts and gene replacements in human cells. Molecular biology of the cell, 29(2), pp.75-83.

Reber, S., Stettler, J., Filosa, G., Colombo, M., Jutzi, D., Lenzken, S. C., Schweingruber, C., Bruggmann, R., Bachi, A., Barabino, S. M., Mühlemann, O. & Ruepp, MD. Minor intron splicing is regulated by FUS and affected by ALS‐associated FUS mutants. The EMBO journal 2016; 35, 14, p. 1504-1521

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