RT Journal Article
SR Electronic
T1 <em>C9orf72</em>-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 835082
DO 10.1101/835082
A1 Laura Fumagalli
A1 Florence L. Young
A1 Steven Boeynaems
A1 Mathias De Decker
A1 Arpan R. Mehta
A1 Ann Swijsen
A1 Raheem Fazal
A1 Wenting Guo
A1 Matthieu Moisse
A1 Jimmy Beckers
A1 Lieselot Dedeene
A1 Bhuvaneish T. Selvaraj
A1 Tijs Vandoorne
A1 Vanesa Madan
A1 Marka van Blitterswijk
A1 Denitza Raitcheva
A1 Alexander McCampbell
A1 Koen Poesen
A1 Aaron D. Gitler
A1 Phillip Koch
A1 Pieter Vanden Berghe
A1 Dietmar Rudolf Thal
A1 Catherine Verfaillie
A1 Siddharthan Chandran
A1 Ludo Van Den Bosch
A1 Simon L. Bullock
A1 Philip Van Damme
YR 2019
UL http://biorxiv.org/content/early/2019/11/20/835082.abstract
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.