Aberrant splicing exonizes C9orf72 repeat expansion in ALS/FTD

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• A GGGGCC nucleotide repeat expansion (NRE) in the C9orf72 gene is a leading cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• The mechanism by which intronic NREs lead to toxic dipeptide repeat (DPR) protein production in the cytoplasm is not fully understood.

Purpose of the Study:

• To elucidate the mechanism of C9 NRE RNA localization and DPR protein production.
• To identify potential therapeutic targets for C9-ALS/FTD.

Main Methods:

• NRE-capture-seq was employed to profile NRE-containing RNAs in patient-derived fibroblasts and neurons.
• Investigated the role of alternative splicing and splicing factors in C9 NRE RNA biogenesis.
• Evaluated the efficacy of antisense oligonucleotides (ASOs) in reducing DPR levels.

Main Results:

• C9 NRE is retained within an extended exon 1 through the use of alternative 5' splice sites, contrary to previous models.
• Aberrant splice isoforms accumulate in C9-ALS/FTD brains and are promoted by SRSF1.
• Targeting SRSF1 or aberrant C9 splice isoforms with ASOs effectively reduced DPR protein levels.

Conclusions:

• Aberrant splicing plays a critical role in the biogenesis of pathogenic C9 NRE-containing RNAs.
• Targeting aberrant splicing and SRSF1 presents a promising therapeutic strategy for C9-ALS/FTD.