PT  - JOURNAL ARTICLE
AU  - Laura Fumagalli
AU  - Florence L. Young
AU  - Steven Boeynaems
AU  - Mathias De Decker
AU  - Arpan R. Mehta
AU  - Ann Swijsen
AU  - Raheem Fazal
AU  - Wenting Guo
AU  - Matthieu Moisse
AU  - Jimmy Beckers
AU  - Lieselot Dedeene
AU  - Bhuvaneish T. Selvaraj
AU  - Tijs Vandoorne
AU  - Vanesa Madan
AU  - Marka van Blitterswijk
AU  - Denitza Raitcheva
AU  - Alexander McCampbell
AU  - Koen Poesen
AU  - Aaron D. Gitler
AU  - Phillip Koch
AU  - Pieter Vanden Berghe
AU  - Dietmar Rudolf Thal
AU  - Catherine Verfaillie
AU  - Siddharthan Chandran
AU  - Ludo Van Den Bosch
AU  - Simon L. Bullock
AU  - Philip Van Damme
TI  - <em>C9orf72</em>-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility
AID  - 10.1101/835082
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 835082
4099  - http://biorxiv.org/content/early/2019/11/20/835082.short
4100  - http://biorxiv.org/content/early/2019/11/20/835082.full
AB  - Hexanucleotide repeat expansions in the C9orf72 gene are 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 use human induced pluripotent stem cell-derived motor neurons to show that C9orf72 repeat expansions impair microtubule-based transport of mitochondria, a process critical for maintenance of neuronal function. Cargo transport defects are recapitulated by treating healthy neurons with the arginine-rich dipeptide repeat proteins (DPRs) that are produced by the hexanucleotide repeat expansions. Single-molecule imaging shows that these DPRs perturb motility of purified kinesin-1 and cytoplasmic dynein-1 motors along microtubules in vitro. Additional in vitro and in vivo data indicate that the DPRs impair transport by interacting with both microtubules and the motor complexes. We also show that kinesin-1 is enriched in DPR inclusions in patient brains and that increasing the level of this motor strongly suppresses the toxic effects of arginine-rich DPR expression in a Drosophila model. Collectively, our study implicates an inhibitory interaction of arginine-rich DPRs with the axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to novel potential therapeutic strategies.