Jonas Mechtersheimer and Daniel Jutzi, students in the research laboratory of NOMIS scientist Marc-David Ruepp, obtained their PhDs in molecular biology on May 1, 2020, and September 1, 2020, respectively, at King’s College London.
Mechtersheimer and Jutzi are two of the first students to participate in a NOMIS Foundation-funded project while completing their PhDs. Both joined the NOMIS project Elucidation of Selective Motor Neuron Death in Amyotrophic Lateral Sclerosis (ALS) led by Ruepp at the University of Bern before relocating with the group to King’s College London and the UK Dementia Research Institute. Ruepp and his team are investigating altered RNA metabolism in neurodegeneration, focusing on how mutations in the gene fused in sarcoma (FUS) lead to ALS.
As part of his outstanding thesis research, Mechtersheimer used CRISPR/Cas9 technology to edit the genome of induced pluripotent stem cells (iPSCs), either by completely removing the FUS gene or by introducing ALS-causing mutations. He then differentiated these iPSCs into motor neurons to study the physiological functions of FUS as well as the impact of disease-causing mutations on RNA metabolism. Besides improving our understanding of FUS’s role in health and disease, his work on genome editing revealed the pitfalls and risks in generating knockouts by nonhomologous end joining (NHEJ), which could invalidate any subsequent data gained, and provided an alternative approach that prevents these issues (Mechtersheimer and Reber et al., 2018; Reber and Mechtersheimer et al., 2018).
Jutzi set out to identify RNAs that are directly bound by FUS and to investigate how ALS-associated mutations affect these interactions. Using a state-of-the-art technique called CLIP, he discovered that FUS primarily interacts with the U1 snRNA, an RNA molecule that plays a central role in gene expression. Furthermore, Jutzi found that in ALS, mutant FUS binds to the U1 snRNA in a toxic manner, preventing other proteins access to the RNA—proteins that are essential for RNA function.
Jutzi and Mechterheimer then joined forces to validate these findings in iPSC-derived FUS-ALS motor neurons and could also show that this process is disturbed in a FUS-ALS mouse model. Their data suggest that toxic RNA interactions of ALS-linked FUS may contribute to the disease and that FUS-linked ALS overlaps pathomechanistically with the motor neuron disease spinal muscular atrophy (SMA). These findings were published in Nature Communications in Dec., 2020.
Creating a spark in the world of science
NOMIS’s mission is to support and enable insight-driven science across all disciplines, focusing on researchers who put forth bold new ideas, exhibit a pioneering spirit and seek to inspire the world around them. Ruepp, who is Mechtersheimer’s and Jutzti’s academic advisor, exemplifies this pioneering spirit through his exceptional scientific capabilities and leadership as well as by enabling a new generation of promising scientists such as Jonas Mechtersheimer and Daniel Jutzi. Congratulations, Dr. Mechtersheimer and Dr. Jutzi!
Senior lecturer in neuroscience
King’s College London
Elucidation of Selective Motor Neuron Death in Amyotrophic Lateral Sclerosis (ALS)
NOMIS RESEARCH PROJECT