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bioRxiv · 10.1101/2020.07.20.211557

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

Tyzack, G. E.·Neeves, J.·Klein, P.·Crerar, H.·Ziff, O.·Taha, D. M.·Luisier, R.·Luscombe, N. M.·Patani, R.
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Abstract

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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/211557v2_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@153fc1eorg.highwire.dtl.DTLVardef@cd3506org.highwire.dtl.DTLVardef@544868org.highwire.dtl.DTLVardef@15ddb68_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Tyzack, G. E., Neeves, J., Klein, P., Crerar, H., Ziff, O., Taha, D. M., Luisier, R., Luscombe, N. M., Patani, R.. 2020-07-21. An aberrant cytoplasmic intron retention programme is a blueprint for ALS-related RBP mislocalization. https://doi.org/10.1101/2020.07.20.211557

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