Prematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS

Loss of SFPQ is a hallmark of motor degeneration in ALS and prevents maturation of motor neurons when occurring during embryogenesis. Here, we show that in zebrafish, developing motor neurons lacking SFPQ exhibit axon extension, branching and synaptogenesis defects, prior to degeneration. Subcellular transcriptomics reveals that loss of SFPQ in neurons produces a complex set of aberrant intron-retaining (IR) transcripts coding for neuron-specific proteins that accumulate in neurites. Some of these local IR mRNAs are prematurely terminated within the retained intron (PreT-IR). PreT-IR mRNAs undergo intronic polyadenylation, nuclear export, and localise to neurites in vitro and in vivo. We find these IR and PreT-IR mRNAs enriched in RNAseq datasets of tissue from patients with familial and sporadic ALS. This shared signature, between SFPQ-depleted neurons and ALS, functionally implicates SFPQ with the disease and suggests that neurite-centred perturbation of alternatively spliced isoforms drives the neurodegenerative process.