Like a city at night, the brain is built from connected neighborhoods that communicate to control how we move, think and interact with the world. Amyotrophic lateral sclerosis (ALS) is a disease in which these connections gradually fail, causing people to lose the ability to walk, talk and eat. In 97% of patients, the protein TDP-43 stops functioning properly, but why this damages neurons remains unknown. We recreate this process in human neurons to uncover new targets for future treatments.
reNEW research
We use human stem cell-derived neurons to investigate what happens just before the lights begin to go out. We engineered human stem cells with a genetic switch that lets us remove TDP-43 at precise moments during brain cell development. This timed knockdown mimics the nuclear loss seen in ALS, letting us track the resulting molecular cascade, including mis-splicing of TDP-43 target genes, step by step, and test strategies to prevent or reverse the damage.
Image description
Human stem cell-derived neurons forming communication networks (yellow) before depletion of TDP-43 (neuronal nuclei, magenta).
Credits
Dr Louise Saviø Piilgaard, Postdoc, Kirkeby lab, reNEW Copenhagen.
