[Sci Adv.]C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

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C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility Sci Adv. 2021 Apr 9;7(15):eabg3013. doi: 10.1126/sciadv.abg3013. Print 2021 Apr. Authors Laura Fumagalli 1 2 , Florence L Young 3 , Steven Boeynaems 4 , Mathias De Decker 1 2 , Arpan R Mehta 5 6 7 8 , Ann Swijsen 1 2 , Raheem Fazal 1 2 , Wenting Guo 1 2 9 , Matthieu Moisse 1 2 , Jimmy Beckers 1 2 , Lieselot Dedeene 1 2 10 11 12 , Bhuvaneish T Selvaraj 5 6 8 , Tijs Vandoorne 1 2 , Vanesa Madan 3 , Marka van Blitterswijk 13 , Denitza Raitcheva 14 , Alexander McCampbell 14 , Koen Poesen 10 12 , Aaron D Gitler 4 , Philipp Koch 15 16 , Pieter Vanden Berghe 17 , Dietmar Rudolf Thal 11 18 , Catherine Verfaillie 9 , Siddharthan Chandran 5 6 7 8 19 20 , Ludo Van Den Bosch 1 2 , Simon L Bullock 21 , Philip Van Damme 22 2 23 Affiliations 1 KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium. 2 VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium. 3 Division of Cell Biology, MRC Laboratory of Molecular Biology, Cambridge, UK. 4 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. 5 UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK. 6 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 7 The Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK. 8 The Euan MacDonald Centre, University of Edinburgh, Edinburgh, UK. 9 KU Leuven-University of Leuven, Department of Development and Regeneration, Stem Cell Institute, Leuven, Belgium. 10 KU Leuven-University of Leuven, Department of Neurosciences, Laboratory for Molecular Neurobiomarker Research and Leuven Brain Institute (LBI), Leuven, Belgium. 11 KU Leuven-University of Leuven, Department of Imaging and Pathology, Laboratory for Neuropathology and Leuven Brain Institute (LBI), Leuven, Belgium. 12 Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium. 13 Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. 14 Biogen Idec, Boston, MA, USA. 15 Hector Institute for Translational Brain Research, Central Institute of Mental Health, University of Heidelberg, Heidelberg, Germany. 16 Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn, Bonn, Germany. 17 KU Leuven-University of Leuven, Translational Research Centre for Gastrointestinal Disorders, Leuven, Belgium. 18 Department of Pathology, University Hospitals Leuven, Leuven, Belgium. 19 Centre for Brain Development and Repair, inStem, Bangalore, India. 20 MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK. 21 Division of Cell Biology, MRC Laboratory of Molecular Biology, Cambridge, UK. philip.vandamme@uzleuven.be sbullock@mrc-lmb.cam.ac.uk. 22 KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium. philip.vandamme@uzleuven.be sbullock@mrc-lmb.cam.ac.uk. 23 Department of Neurology, University Hospitals Leuven, Leuven, Belgium. PMID: 33837088 DOI: 10.1126/sciadv.abg3013 Abstract 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. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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