C9orf72 ALS-causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules

  • FEBS Lett. 2025 Sep 1. doi: 10.1002/1873-3468.70156.
Saygın Bilican  1  2 ,  Yara Nabawi  1  2 ,  William Hongyu Zhang  1  2 ,  Dunja Petrovic  1  2 ,  Markus Wehrmann  1  2 ,  Sara Muñoz-García  2 ,  Seda Koyuncu  1  2 ,  David Vilchez  1  2  3  4
Affiliations
  • 1. Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Germany.
  • 2. Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.
  • 3. Institute for Genetics, University of Cologne, Germany.
  • 4. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
PMID: 40891053 DOI: 10.1002/1873-3468.70156
Abstract

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.

Keywords
Amyotrophic lateral sclerosis; C. elegans; Nucleoporins; Proteostasis; Stress granules; iPSC‐disease modeling.
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