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

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Abstract

Arginine-rich dipeptide repeats associated with ALS and FTD inhibit machinery for microtubule-based axonal cargo transport.

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.

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Accurate Proteome-wide Label-free Quantification by Delayed Normalization and Maximal Peptide Ratio Extraction, Termed MaxLFQ *

Jürgen Cox, Marco Y. Hein, Christian A. Luber … (2014)

Protein quantification without isotopic labels has been a long-standing interest in the proteomics field. However, accurate and robust proteome-wide quantification with label-free approaches remains a challenge. We developed a new intensity determination and normalization procedure called MaxLFQ that is fully compatible with any peptide or protein separation prior to LC-MS analysis. Protein abundance profiles are assembled using the maximum possible information from MS signals, given that the presence of quantifiable peptides varies from sample to sample. For a benchmark dataset with two proteomes mixed at known ratios, we accurately detected the mixing ratio over the entire protein expression range, with greater precision for abundant proteins. The significance of individual label-free quantifications was obtained via a t test approach. For a second benchmark dataset, we accurately quantify fold changes over several orders of magnitude, a task that is challenging with label-based methods. MaxLFQ is a generic label-free quantification technology that is readily applicable to many biological questions; it is compatible with standard statistical analysis workflows, and it has been validated in many and diverse biological projects. Our algorithms can handle very large experiments of 500+ samples in a manageable computing time. It is implemented in the freely available MaxQuant computational proteomics platform and works completely seamlessly at the click of a button.

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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.

Mariely DeJesus-Hernandez, Ian R. Mackenzie, Bradley F. Boeve … (2011)

Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS. Copyright © 2011 Elsevier Inc. All rights reserved.

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A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.

Alan E. Renton, Elisa Majounie, Adrian Waite … (2011)

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date. Copyright © 2011 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: April 2021

Publication date (Electronic): 09 April 2021

Volume: 7

Issue: 15

Electronic Location Identifier: eabg3013

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 ]Department of Neurology, University Hospitals Leuven, Leuven, Belgium.

Author notes

[* ]Corresponding author. Email: philip.vandamme@ 123456uzleuven.be (P.V.D.); sbullock@ 123456mrc-lmb.cam.ac.uk (S.L.B.)

[†]

These authors contributed equally to this work.

Author information

Laura Fumagalli http://orcid.org/0000-0002-9333-926X

Florence L. Young http://orcid.org/0000-0002-5475-9835

Steven Boeynaems http://orcid.org/0000-0002-9705-9871

Arpan R. Mehta http://orcid.org/0000-0002-5715-5025

Raheem Fazal http://orcid.org/0000-0001-8833-9997

Wenting Guo http://orcid.org/0000-0003-3585-7728

Matthieu Moisse http://orcid.org/0000-0001-8880-9311

Lieselot Dedeene http://orcid.org/0000-0003-0545-8072

Bhuvaneish T. Selvaraj http://orcid.org/0000-0001-7299-0910

Marka van Blitterswijk http://orcid.org/0000-0002-3054-7053

Denitza Raitcheva http://orcid.org/0000-0001-9003-9168

Alexander McCampbell http://orcid.org/0000-0002-1984-6052

Aaron D. Gitler http://orcid.org/0000-0001-8603-1526

Philipp Koch http://orcid.org/0000-0003-3713-8786

Pieter Vanden Berghe http://orcid.org/0000-0002-0009-2094

Dietmar Rudolf Thal http://orcid.org/0000-0002-1036-1075

Catherine Verfaillie http://orcid.org/0000-0001-7564-4079

Ludo Van Den Bosch http://orcid.org/0000-0003-0104-4067

Simon L. Bullock http://orcid.org/0000-0001-9491-4548

Philip Van Damme http://orcid.org/0000-0002-4010-2357

Article

Publisher ID: abg3013

DOI: 10.1126/sciadv.abg3013

PMC ID: 8034861

PubMed ID: 33837088

SO-VID: 0ae19731-f7e3-4d97-9b1a-a2b6b9fc06e6

Copyright © 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).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 23 December 2020

Date accepted : 23 February 2021

Funding

Funded by: doi http://dx.doi.org/10.13039/501100000265, Medical Research Council;

Award ID: MC_U105178790

Funded by: doi http://dx.doi.org/10.13039/501100000406, Motor Neurone Disease Association;

Award ID: MR/R001162/1