New study uncovers a breakthrough in the understanding of motor neuron death in ALS

Amyotrophic lateral sclerosis (ALS), also known as Motor Neuron Disease, is a devastating neurological disease that causes motor neurons to die, leading to muscle weakness and ultimately death. It has been challenging to access motor neurons to identify the underlying causes of the disease, due to high risk of complications that come with a biopsy of the fragile spinal cord. Researchers have turned to studying motor neurons derived from induced pluripotent stem cells (iPSC) to better understand ALS. However, previous iPSC studies were limited to small numbers of patients, and there is no consensus on how ALS develops.

In this study, researchers led by Professor Rickie Patani (Professor of Human Stem Cells and Regenerative Neurology at UCL Queen Square Institute of Neurology and The Francis Crick Institute) and Dr Ziff (Crick Clinical PhD Research Fellow) combined iPSC-derived motor neurons and post-mortem spinal cord tissue data into a large resource, to identify changes that cause motor neuron death in ALS. They found that ALS leads to an accumulation of somatic mutations and a heightened DNA damage response. Although these changes were observed in various types of ALS, they were most notable in cases where the nuclear protein, TDP-43, was relocated to the cytoplasm. This study highlights genome instability as a hallmark of ALS and could help in the development of new therapies.

"Our study adds to mounting evidence linking p53 activation - which may serve as an initial protective response to DNA damage - to the death of motor neurons in ALS. By analysing hundreds of iPSC-motor neurons and post-mortem spinal cord samples, we identified a consistently heightened DNA damage response across different ALS subtypes. This finding could lead to new strategies for preventing motor neuron loss and slowing the progression of ALS." Dr Oliver Ziff

Links

• Ziff, O.J., Neeves, J., Mitchell, J. et al. Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology. Nat Commun 14, 2176 (2023). https://doi.org/10.1038/s41467-023-37630-6
• Professor Patani's academic profile
• Dr Ziff's academic profile
• UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology

Image

• Study overview: Schematic summarising analytic framework using iPSC-derived motor neurons (iPSMNs) and post-mortem tissue to interrogate perturbations across the spectrum of ALS. Made with BioRender.