Abstract
The RNA-binding protein SFPQ plays an important role in neuronal development and has been associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease. Here, we report that loss of sfpq leads to premature termination of multiple transcripts due to widespread activation of previously unannotated cryptic last exons (CLEs). These SFPQ-inhibited CLEs appear preferentially in long introns of genes with neuronal functions and can dampen gene expression outputs and/or give rise to short peptides interfering with the normal gene functions. We show that one such peptide encoded by the CLE-containing epha4b mRNA isoform is responsible for neurodevelopmental defects in the sfpq mutant. The uncovered CLE-repressive activity of SFPQ is conserved in mouse and human, and SFPQ-inhibited CLEs are found expressed across ALS iPSC-derived neurons. These results greatly expand our understanding of SFPQ function and uncover a gene regulation mechanism with wide relevance to human neuropathologies.
Highlights
The RNA-binding protein SFPQ plays an important role in neuronal development and has been associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease
The analysis confirmed that alternate last exons are the most abundant category of SFPQ-regulated splicing events accounting for 18.5% of the total (Fig. 1c)
We show that cryptic last exons (CLEs) are functionally relevant as regulators of gene expression output or/and a mechanism for producing deleterious protein isoforms
Summary
The RNA-binding protein SFPQ plays an important role in neuronal development and has been associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease. We report that loss of sfpq leads to premature termination of multiple transcripts due to widespread activation of previously unannotated cryptic last exons (CLEs) These SFPQ-inhibited CLEs appear preferentially in long introns of genes with neuronal functions and can dampen gene expression outputs and/or give rise to short peptides interfering with the normal gene functions. Our results reveal an important role for the protein: loss of SFPQ causes premature termination of transcription as a result of previously unannotated pre-mRNA processing events that we refer to as Cryptic Last Exons (CLEs). We describe the formation of CLEs and show that do the truncated transcripts act as a form of negative regulation of gene expression levels, but they directly contribute to the sfpq pathology This function of SFPQ is conserved across vertebrates and is likely to be implicated in human SFPQ-mediated disease states
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