C9orf72ALS‐causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules

Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by motor neuron degeneration. Hexanucleotide repeat expansions in the C9orf72 gene, the most common genetic cause of ALS (C9‐ALS), drive toxicity through different mechanisms. These pathological changes include alterations in stress granules (SGs), ribonucleoprotein complexes formed under stress conditions. Here, we show that G3BP1, a core component of SGs, exhibits enhanced interaction with the nucleoporin Nup107 in motor neurons derived from patient iPSCs carrying C9orf72 mutations. Moreover, Nup107 colocalizes with SGs and aggregates in C9‐ALS motor neurons. Notably, knockdown of npp‐5 , the Caenorhabditis elegans ortholog of Nup107, alleviates ALS‐associated phenotypes in worm models, including reduced lifespan and impaired motility. Together, our findings provide insights into disease‐related changes in C9‐ALS pathogenesis.