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An aberrant cytoplasmic intron retention programme is a blueprint for ALS-related RBP mislocalization

ABSTRACT: An aberrant cytoplasmic intron retention programme is a blueprint for ALS-related RBP mislocalization

PROVIDER: PRJNA641118 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12068300_1.fastq.gz	Fastqsanger.gz
	SRR12068300_2.fastq.gz	Fastqsanger.gz
	SRR12068400_1.fastq.gz	Fastqsanger.gz
	SRR12068400_2.fastq.gz	Fastqsanger.gz
	SRR12068500_1.fastq.gz	Fastqsanger.gz

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An aberrant cytoplasmic intron retention programme is a blueprint for ALS-related RBP mislocalization

Project description:We recently described aberrant cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as a new hallmark of amyotrophic lateral sclerosis (ALS). However the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep-sequencing of nuclear and cytoplasmic fractions of hiPSCs undergoing motor neurogenesis, we reveal that ALS-causing VCP gene mutations lead to compartment-specific aberrant accumulation of IRTs. Specifically, we identify >100 IRTs with increased cytoplasmic (but not nuclear) abundance in ALS samples. Furthermore, these aberrant cytoplasmic IRTs possess sequence-specific attributes and differential predicted binding affinity to RNA binding proteins (RBPs). Remarkably, TDP-43, SFPQ and FUS - RBPs known for nuclear-to-cytoplasmic mislocalization in ALS - avidly and specifically bind to this aberrant cytoplasmic pool of IRTs, as opposed to any individual IRT. Our data are therefore consistent with a novel role for cytoplasmic IRTs in regulating compartment-specific protein abundance. This study provides new molecular insight into potential pathomechanisms underlying ALS and highlights aberrant cytoplasmic IRTs as potential therapeutic targets.

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Aberrant cytoplasmic intron retention is a blueprint for RNA binding protein mislocalization in VCP-related amyotrophic lateral sclerosis.

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