Abstract
Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1 specifically inhibits the nuclear export of pathological C9ORF72 transcripts, the production of dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons and neuronal cell models. Taken together, we show that repeat RNA-sequestration of SRSF1 triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded hexanucleotide repeats and reveal a novel promising therapeutic target for neuroprotection.
Highlights
Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia
As shown on the Phosphoimages, covalently-bound RNA molecules remained associated with ALYREF and SRSF1 visualized on the Coomassie-stained panels during the denaturing electrophoresis
The production of toxic polymeric repeat proteins by repeatassociated non-ATG (RAN) translation has been characterized in multiple neurodegenerative disorders caused by microsatellite expansions including spinocerebellar ataxia type 8 (SCA8)[58], myotonic dystrophy type 1 (DM1)[58], Fragile X-associated tremor and ataxia syndrome (FXTAS)[59], C9ORF72-ALS6,13–16,27 and Huntington disease (HD)[60]
Summary
Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. We show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1 inhibits the nuclear export of pathological C9ORF72 transcripts, the production of dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons and neuronal cell models. A small proportion of C9ORF72 repeat transcripts retaining pathological repeat expansions in intron-1 escape nuclear retention mechanisms and were detected in the cytoplasm of patientderived lymphoblasts[28] where they can subsequently be translated into DPRs. Interestingly, nucleocytoplasmic transport defects of proteins and RNA were recently highlighted in Drosophila, yeast and human neuronal models of C9ORF72-related ALS29–32. We refer to references[47,48] for recent reviews on TREX and the nuclear export of mRNA
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