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

Autor: Castelli LM; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Lin YH; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Sanchez-Martinez A; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK., Gül A; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Mohd Imran K; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Higginbottom A; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Upadhyay SK; Leicester Institute of Structural and Chemical Biology and Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK., Márkus NM; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Rua Martins R; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Cooper-Knock J; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Montmasson C; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Cohen R; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Walton A; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Bauer CS; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., De Vos KJ; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Mead RJ; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Azzouz M; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Dominguez C; Leicester Institute of Structural and Chemical Biology and Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK., Ferraiuolo L; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Shaw PJ; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK., Whitworth AJ; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK., Hautbergue GM; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2023 Mar; Vol. 15 (685), pp. eabo3823. Date of Electronic Publication: 2023 Mar 01.
DOI: 10.1126/scitranslmed.abo3823
Abstrakt: 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.
Databáze: MEDLINE
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