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- Title
A cell-penetrant peptide blocking C9ORF72-repeat RNA nuclear export reduces the neurotoxic effects of dipeptide repeat proteins.
- Authors
Castelli, Lydia M.; Lin, Ya-Hui; Sanchez-Martinez, Alvaro; Gül, Aytaç; Mohd Imran, Kamallia; Higginbottom, Adrian; Upadhyay, Santosh Kumar; Márkus, Nóra M.; Rua Martins, Raquel; Cooper-Knock, Johnathan; Montmasson, Claire; Cohen, Rebecca; Walton, Amy; Bauer, Claudia S.; De Vos, Kurt J.; Mead, Richard J.; Azzouz, Mimoun; Dominguez, Cyril; Ferraiuolo, Laura; Shaw, Pamela J.
- Abstract
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. House arrest for toxic C9ORF72 hexanucleotide repeat expanded RNAs: Hexanucleotide repeat expansions in the C9ORF72 gene, and translation of these repeat transcripts into toxic dipeptide repeat proteins (DPRs) causes neurodegeneration in some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Castelli et al. report that a peptide that prevents the nuclear exit of pathological C9ORF72-repeat RNAs inhibits the production of DPRs in rat and human cell models. The peptide also blocked neurotoxic DPR production in flies and mice in vivo and ameliorated locomotor deficits in a fly disease model. This suggests that blocking nuclear export of toxic C9ORF72-repeat RNAs could be a potential therapeutic strategy to reduce neurodegeneration in ALS and FTD. —DN
- Subjects
PEPTIDES; AMYOTROPHIC lateral sclerosis; TRYPANOSOMIASIS; ORAL drug administration; NUCLEOCYTOPLASMIC interactions; GENETIC translation; INTRATHECAL injections; DIPEPTIDES; RNA metabolism
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 685, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abo3823