Marc-David Ruepp

marc-david.ruepp@kcl.ac.uk

RueppLab

Website

Research Interests

The research in our lab centers around RNA metabolism in health and disease, with Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) as primary focuses. We are particularly invested in the study of the molecular determinants of FUS toxicity in FUS-linked ALS and converging pathomechanisms across the ALS/FTD spectrum. To this end, we use a combination of biochemical, molecular, and cell biology methods coupled with in vitro and in vivo disease modeling using genome-edited isogenic de novo ALS human induced pluripotent stem cells and mouse models. With our research, we aim at closing the mechanistic knowledge gaps in ALS/FTD in order to identify patho-mechanisms and disease-relevant pathways, followed by testing identified targets in preclinical research packages to evaluate their potential to alleviate and prevent neurodegeneration.

Most significant discovery

We uncovered the U1 snRNA as primary RNA target of FUS and that ALS-FUS engages in a RNAbased toxic interaction with the U1 snRNA in the cytoplasm with the potential to cause or
contribute to motor neuron degradation. This work also provided a molecular link between
ALS-FUS and Spinal Muscular Atrophy via dysfunctional snRNP metabolism.

Educational Interests

• RNA splicing in health and disease
• Liquid-liquid phase separation in health and
neurodegenerative disease
• Experimental Topics in Neuroscience

Top 4 Publications

• Reber S, et al. Nucleic Acids Res. 2021 Jul 21;49(13):7713-7731.
• Jutzi, D., et al. Nat Commun. Dec 11;11(1):6341.
• Loughlin F, et al. Mol Cell 2019; 73, 3, p. 490-504.e6
• Reber S, et al. Mol Biol Cell 29(2), pp.75-83.

Methods / Expertise

• Genome editing using CRISPR/Cas9
• CRISPR-Trap
• Disease modelling using human iPSCs
• Pre-mRNA processing
• Splicing modulation with chimeric snRNAs
• Liquid-liquid phase separation
• Molecular biology