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

Autor:	Tyzack GE; Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK., Neeves J; Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK., Crerar H; Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK., Klein P; Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK., Ziff O; Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK., Taha DM; Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.; Zoology Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt., Luisier R; Genomics and Health Informatics Group, Idiap Research Institute, CH - 1920 Martigny, Switzerland., Luscombe NM; Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.; UCL Genetics Institute, University College London, London, WC1E 6BT, UK.; Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan., Patani R; Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2021 Aug 17; Vol. 144 (7), pp. 1985-1993.
DOI:	10.1093/brain/awab078
Abstrakt:	We recently described aberrantly increased cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as new hallmarks 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 human induced pluripotent stem cells 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 abundance in ALS samples. Furthermore, these aberrant cytoplasmic IRTs possess sequence-specific attributes and differential predicted binding affinity to RNA binding proteins. Remarkably, TDP-43, SFPQ and FUS-RNA binding proteins known for nuclear-to-cytoplasmic mislocalization in ALS-abundantly and specifically bind to this aberrant cytoplasmic pool of IRTs. 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. (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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