"They focused on UPF1, a protein that acts like a proofreader, scanning RNA and destroying defective copies before they cause trouble. This process, called mRNA decay, is essential for healthy cells. The team discovered that UPF1 and TDP-43 normally work together to control the length of RNA messages - especially at their tail ends. These regions help regulate how long an RNA message lasts and where it goes in the cell. In ALS, these processes go haywire, leading to unstable RNA and stressed neurons."
""In most ALS patients, we know that a predominantly nuclear RNA-binding protein known as TDP-43 leaves the nucleus and forms cytoplasmic aggregates," Kiskinis said. "This misslocalization of TDP-43 underlies the pathophysiology of the disease. In this study, we focused on understanding how loss-of-function of TDP-43 in human motor neurons affects RNA metabolism." In the study, Kiskinis and collaborators examined motor neurons derived from induced pluripotent stem cells."
Motor neurons derived from induced pluripotent stem cells show disrupted RNA quality control in ALS. UPF1 functions as an mRNA proofreader that scans and destroys defective RNA through mRNA decay. UPF1 and TDP-43 cooperate to control RNA message length, particularly at 3' tail regions that regulate stability and localization. TDP-43 mislocalization and depletion reduce UPF1 activity, disrupting tail regulation and mRNA decay. Resulting unstable RNAs accumulate and promote neuronal stress. UPF1 activity is significantly diminished in motor neurons from ALS patients, and UPF1–TDP-43 interactions are RNA-dependent. These alterations contribute to hallmark pathology and progressive motor neuron dysfunction.
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