C9orf72 ALS-causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules
Summary
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. © 2025 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
| Authors | Bilican S, Nabawi Y, Zhang WH, Petrovic D, Wehrmann M, Muñoz-García S, Koyuncu S, Vilchez D |
|---|---|
| Journal | FEBS letters |
| Publication Date | 2025 Nov;599(21):3047-3065 |
| PubMed | 40891053 |
| PubMed Central | PMC12599624 |
| DOI | 10.1002/1873-3468.70156 |