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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Sanchez-Martinez, Alvaro  ORCID logo  https://orcid.org/0000-0002-2728-6251
Gül, Aytaç 
Mohd Imran, Kamallia  ORCID logo  https://orcid.org/0000-0002-3719-7826

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.

Description

Keywords

Humans, Animals, Mice, Dipeptides, Amyotrophic Lateral Sclerosis, C9orf72 Protein, Frontotemporal Dementia, Active Transport, Cell Nucleus, HEK293 Cells, Peptides, Motor Neurons, RNA, Serine-Arginine Splicing Factors

Journal Title

Sci Transl Med

Conference Name

Journal ISSN

1946-6234
1946-6242

Volume Title

15

Publisher

American Association for the Advancement of Science (AAAS)
Sponsorship
European Research Council (309742)