2. Academic Validation
  3. C9orf72 ALS-causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules

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

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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