C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

Laura Fumagalli, Florence L. Young, Steven Boeynaems, Mathias De Decker, Arpan R. Mehta, Ann Swijsen, Raheem Fazal, Wenting Guo, Matthieu Moisse, Jimmy Beckers, Lieselot Dedeene, Bhuvaneish T. Selvaraj, Tijs Vandoorne, Vanesa Madan, Marka van Blitterswijk, Denitza Raitcheva, Alexander McCampbell, Koen Poesen, Aaron D. Gitler, Philipp KochPieter Vanden Berghe, Dietmar Rudolf Thal, Catherine Verfaillie, Siddharthan Chandran, Ludo Van Den Bosch, Simon L. Bullock (Lead / Corresponding author), Philip Van Damme (Lead / Corresponding author)

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A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell-derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. Cargo transport defects are recapitulated by treating neurons from healthy individuals with proline-arginine and glycine-arginine dipeptide repeats (DPRs) produced from the repeat expansion. Both arginine-rich DPRs similarly inhibit axonal trafficking in adult Drosophila neurons in vivo. Physical interaction studies demonstrate that arginine-rich DPRs associate with motor complexes and the unstructured tubulin tails of microtubules. Single-molecule imaging reveals that microtubule-bound arginine-rich DPRs directly impede translocation of purified dynein and kinesin-1 motor complexes. Collectively, our study implicates inhibitory interactions of arginine-rich DPRs with axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to potential therapeutic strategies.

Original languageEnglish
Article numberabg3013
Number of pages21
JournalScience Advances
Issue number15
Early online date9 Apr 2021
Publication statusPublished - Apr 2021


  • Amyotrophic Lateral Sclerosis/genetics
  • Animals
  • Arginine/genetics
  • Axonal Transport
  • C9orf72 Protein/genetics
  • DNA Repeat Expansion
  • Dipeptides/pharmacology
  • Drosophila/genetics
  • Frontotemporal Dementia/genetics
  • Humans
  • Microtubules/metabolism
  • Motor Neurons/metabolism


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