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A cell-penetrant peptide blocking C9ORF72-repeat RNA nuclear export reduces the neurotoxic effects of dipeptide repeat proteins

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posted on 2023-05-15, 15:48 authored by LM Castelli, YH Lin, A Sanchez-Martinez, A Gül, K Mohd Imran, A Higginbottom, SK Upadhyay, NM Márkus, R Rua Martins, J Cooper-Knock, C Montmasson, R Cohen, A Walton, CS Bauer, KJ De Vos, RJ Mead, M Azzouz, C Dominguez, L Ferraiuolo, PJ Shaw, AJ Whitworth, GM Hautbergue
Hexanucleotide repeat expansions in C9ORF72 are the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies have shown that the hexanucleotide expansions cause the noncanonical translation of C9ORF72 transcripts into neurotoxic dipeptide repeat proteins (DPRs) that contribute to neurodegeneration. We show that a cell-penetrant peptide blocked the nuclear export of C9ORF72-repeat transcripts in HEK293T cells by competing with the interaction between SR-rich splicing factor 1 (SRSF1) and nuclear export factor 1 (NXF1). The cell-penetrant peptide also blocked the translation of toxic DPRs in neurons differentiated from induced neural progenitor cells (iNPCs), which were derived from individuals carrying C9ORF72-linked ALS mutations. This peptide also increased survival of iNPC-differentiated C9ORF72-ALS motor neurons cocultured with astrocytes. Oral administration of the cell-penetrant peptide reduced DPR translation and rescued locomotor deficits in a Drosophila model of mutant C9ORF72-mediated ALS/FTD. Intrathecal injection of this peptide into the brains of ALS/FTD mice carrying a C9ORF72 mutation resulted in reduced expression of DPRs in mouse brains. These findings demonstrate that disrupting the production of DPRs in cellular and animal models of ALS/FTD might be a strategy to ameliorate neurodegeneration in these diseases.

Funding

Novel therapeutic strategies to target RAN translation of pathological C9ORF72 repeat transcripts and associated neurodegeneration

Medical Research Council

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Structural and functional investigation of the SRSF1-mediated nuclear export of mRNAs

Biotechnology and Biological Sciences Research Council

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Structural and functional investigation of the SRSF1-mediated nuclear export of mRNAs

Biotechnology and Biological Sciences Research Council

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MND Association grant Hautbergue/Apr16/846-791

MRC core funding MC_UU_00028/6 and ERC Starting Grant DYNAMITO: 309742

The involvement of exosomal RNA in astrocyte-mediated toxicity in motor neurone disease

Academy of Medical Sciences

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Identification of therapeutic targets in C9orf72-linked FTD and MND

UK Research and Innovation

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Governmental Turkish Doctoral Scholarship

LifeArc/MND Association grant

NIHR Senior Investigator NF-SI-0617-10077

MND Association AMBRoSIA MNDAOct15/972-797 MRC Centres of Excellence for Neurodegeneration Pathfinder award MR/SOO4920/1

Thierry Latran Foundation FTLAAP2016/Astrocyte secretome

Alzheimer’s Research UK ARUK-PG2018B-005

European Research Council ERC Advanced Award 294745

MRC DPFS 129016

Role of microtubule acetylation in Parkinson's disease

Medical Research Council

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REGULATION OF ER-MITOCHONDRIA CONTACTS IN NEURODEGENERATION

Medical Research Council

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History

Author affiliation

Leicester Institute of Structural & Chemical Biology and Department of Molecular & Cell Biology, University of Leicester

Version

  • AM (Accepted Manuscript)

Published in

Science translational medicine

Volume

15

Issue

685

Pagination

eabo3823

Publisher

American Association for the Advancement of Science (AAAS)

issn

1946-6234

eissn

1946-6242

Copyright date

2023

Available date

2023-05-15

Spatial coverage

United States

Language

eng

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