Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis

Brain : a Journal of Neurology
Giulia E TyzackRickie Patani

Abstract

Mutations causing amyotrophic lateral sclerosis (ALS) clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins, which form pathological cytoplasmic inclusions in this context. However, the possibility that wild-type RNA binding proteins mislocalize without necessarily becoming constituents of cytoplasmic inclusions themselves remains relatively unexplored. We hypothesized that nuclear-to-cytoplasmic mislocalization of the RNA binding protein fused in sarcoma (FUS), in an unaggregated state, may occur more widely in ALS than previously recognized. To address this hypothesis, we analysed motor neurons from a human ALS induced-pluripotent stem cell model caused by the VCP mutation. Additionally, we examined mouse transgenic models and post-mortem tissue from human sporadic ALS cases. We report nuclear-to-cytoplasmic mislocalization of FUS in both VCP-mutation related ALS and, crucially, in sporadic ALS spinal cord tissue from multiple cases. Furthermore, we provide evidence that FUS protein binds to an aberrantly retained intron within the SFPQ transcript, which is exported from the nucleus into the cytoplasm. Collectively, these data support a model for ALS pathogenesis whereby aberrant intron reten...Continue Reading

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Citations

Mar 7, 2020·Journal of Neuropathology and Experimental Neurology·Kensuke IkenakaGen Sobue
Dec 19, 2019·Brain : a Journal of Neurology·Virenkumar A Pandya, Rickie Patani
Aug 5, 2020·Expert Opinion on Therapeutic Targets·Yiran Wang, Rickie Patani
Sep 10, 2019·Brain : a Journal of Neurology·Marta Vidal, Julie D Atkin
Jun 18, 2020·Frontiers in Molecular Neuroscience·Yuan Chao XueHonglin Luo
Aug 28, 2020·Brain : a Journal of Neurology·Rickie Patani
Nov 27, 2019·International Journal of Molecular Sciences·Huijuan LiYulong Sun
Feb 20, 2020·Environmental Science and Pollution Research International·Abdelmagid M ElmatbolyMohamed M Abdel-Daim
Feb 23, 2020·Neurochemical Research·Stephen MooreRita Sattler
Jul 7, 2020·Frontiers in Neuroscience·Zeynep I GunesSabine Liebscher
Aug 10, 2020·Brain : a Journal of Neurology·Shinsuke IshigakiGen Sobue
Nov 2, 2019·Scientific Reports·Joni VannesteLudo Van Den Bosch
Aug 18, 2020·Molecular Neurodegeneration·Terry R Suk, Maxime W C Rousseaux
Aug 28, 2020·Brain : a Journal of Neurology·Giulia E TyzackRickie Patani
Nov 12, 2020·International Journal of Molecular Sciences·Jasmine Harley, Rickie Patani
Oct 2, 2020·International Journal of Molecular Sciences·Yee Wa LimMihwa Lee
Jan 16, 2021·Journal of Neuropathology and Experimental Neurology·Barbara SzewczykAndreas Hermann
Feb 13, 2021·Brain Pathology·Cathleen HagemannRaphaëlle Luisier
Sep 26, 2020·Journal of Molecular Cell Biology·Donya PakravanLudo Van Den Bosch
Jan 23, 2021·International Journal of Molecular Sciences·Sophie LayalleLaurent Soustelle
Jan 12, 2021·Brain : a Journal of Neurology·Benjamin E Clarke, Rickie Patani
Apr 4, 2021·International Journal of Molecular Sciences·Wanil KimKyung-Ha Lee
Apr 24, 2021·Stem Cell Reports·Katarina Stoklund DittlauLudo Van Den Bosch
Sep 8, 2021·Nature Communications·Hitoki NanauraEiichiro Mori
Sep 8, 2021·Molecular Neurodegeneration·Inmaculada Sanjuan-RuizLuc Dupuis
Oct 2, 2021·Neuropathology and Applied Neurobiology·Colombine VerzatRaphaëlle Luisier

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Methods Mentioned

BETA
transgenic
PCR
electrophoresis
iCLIP
immunoprecipitation
smFISH

Software Mentioned

Cutadapt
Probe Designer
Fiji
Bowtie2
STAR

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