Abstract

Microsatellite repeat expansions cause several incurable and lethal neurodegenerative disorders including ataxias, myotonic dystrophy, Huntington's disease and C9ORF72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Abnormal repeat transcripts generated from the expanded loci are substrates of repeat-associated non-AUG (RAN) translation, an unconventional form of translation leading to the production of polymeric repeat proteins with cytotoxic and aggregating properties. The mechanisms involved in the pathogenesis of microsatellite repeat expansion disorders remain a hotly debated topic. They are shared between toxic loss/gain of functions due to intranuclear RNA foci that sequesters RNA-binding proteins and RAN translation of repeat proteins in the cytoplasm. We recently elucidated the molecular mechanism driving the nuclear export of C9ORF72 repeat transcripts and showed for the first time that this pathway can be manipulated to confer neuroprotection. Strikingly, we discovered that intron-retaining C9ORF72 repeat transcripts hijack the physiological NXF1-dependent export pathway by selective RNA-repeat sequestration of SRSF1. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the survival of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in Drosophila (Hautbergue et al. Nature Communications 2017; 8:16063). In this invited Research Highlight review, we aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a summary of the published research and highlight the significance of these findings as a novel therapeutic strategy for neuroprotection in C9ORF72-ALS/FTD. In addition, we emphasize that protein sequestration, often thought as of inducing loss-of-function mechanisms, can also trigger unwanted protein interactions and toxic gain-of-functions.

Highlights

  • The pathophysiology leading to neuronal injury is complex and potentially involves three non-exclusive mechanisms of pathogenesis which have been extensively studied

  • RNA polymerase II (RNAPII)-dependent transcription involves the assembly of a pre-initiation complex upstream of the transcription start site (TSS) in the promoters of protein-coding genes, following recognition of the TATA box element by the TATA box binding protein (TBP), a subunit of the general transcription factor TFIID, which triggers the recruitment of additional general transcription factors and the hypo-phosphorylated form of the RNAPII (RNAPIIA)

  • Splicing of introns is linked to the deposition of the RNA/ATP-dependent DEAD-box RNA helicase 39B (DDX39B known as UAP56 for U2AF65-associated protein 56), which promotes the assembly of spliceosomes via interactions with the carboxyl-terminal domain (CTD) predominantly phosphorylated mRNAs produced from intron-containing reporter constructs are more efficiently exported into the cytoplasm of mammalian cells [15]

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Summary

RESEARCH HIGHLIGHT

SRSF1-dependent nuclear export of C9ORF72 repeat-transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the survival of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in Drosophila (Hautbergue et al Nature Communications 2017; 8:16063) In this invited Research Highlight review, we aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a summary of the published research and highlight the significance of these findings as a novel therapeutic strategy for neuroprotection in C9ORF72-ALS/FTD. The pathophysiology leading to neuronal injury is complex and potentially involves three non-exclusive mechanisms of pathogenesis which have been extensively studied (reviewed in [5, 6]) These include: (i) RNA toxic gain-of-functions by sequestration of RNA-processing factors onto hexanucleotide-repeat RNAs, (ii) protein toxic gain-of-function due to unconventional repeat-associated non-AUG (RAN) translation of cytotoxic dipeptide-repeat proteins (DPRs) in all frames and in the absence of canonical start codons, and (iii) haploinsufficiency due to reduced expression levels of C9ORF72 mRNA and protein. We hypothesized that the sequestration of these nuclear export adaptors might license the inappropriate nuclear export of intron-retaining C9ORF72 repeat transcripts and subsequently lead to the RAN translation of DPRs in the cytoplasm [8]

The nuclear export of bulk mRNAs
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