Proteomics analysis of FUS mutant human motoneurons reveals altered regulation of cytoskeleton and other ALS-linked proteins via 3'UTR binding.

Scientific Reports
Maria G GaroneAlessandro Rosa

Abstract

Increasing evidence suggests that in Amyotrophic Lateral Sclerosis (ALS) mutated RNA binding proteins acquire aberrant functions, leading to altered RNA metabolism with significant impact on encoded protein levels. Here, by taking advantage of a human induced pluripotent stem cell-based model, we aimed to gain insights on the impact of ALS mutant FUS on the motoneuron proteome. Label-free proteomics analysis by mass-spectrometry revealed upregulation of proteins involved in catabolic processes and oxidation-reduction, and downregulation of cytoskeletal proteins and factors directing neuron projection. Mechanistically, proteome alteration does not correlate with transcriptome changes. Rather, we observed a strong correlation with selective binding of mutant FUS to target mRNAs in their 3'UTR. Novel validated targets, selectively bound by mutant FUS, include genes previously involved in familial or sporadic ALS, such as VCP, and regulators of membrane trafficking and cytoskeleton remodeling, such as ASAP1. These findings unveil a novel mechanism by which mutant FUS might intersect other pathogenic pathways in ALS patients' motoneurons.

References

Mar 22, 2000·Proceedings of the National Academy of Sciences of the United States of America·P A RandazzoJ A Cooper
Jan 22, 2002·Trends in Neurosciences·Holger Patzke, Li Huei Tsai
Apr 20, 2010·Human Molecular Genetics·Clotilde Lagier-TourenneDon W Cleveland
Jul 8, 2010·The EMBO Journal·Dorothee DormannChristian Haass
Jun 28, 2011·Trends in Neurosciences·Dorothee Dormann, Christian Haass
Jul 11, 2012·Proceedings of the National Academy of Sciences of the United States of America·Zi Chao Zhang, Yuh Min Chook
Nov 16, 2012·Neurology·Paloma González-PérezSergiu C Blumen
Jun 12, 2013·Nucleic Acids Research·Daniel D'AndreaAnna Tramontano
Oct 1, 2013·Neurochemical Research·Magdalena Kuźma-KozakiewiczAnna Barańczyk-Kuźma
Dec 9, 2014·Methods : a Companion to Methods in Enzymology·Sune Pletscher-FrankildLars Juhl Jensen
Jan 7, 2015·Proteomics·Qiang HuangYaoyang Zhang
Apr 22, 2015·Journal of Neurology·Viviana PensatoUNKNOWN SLAGEN Consortium
Jan 1, 2014·Scientific Data·George RosenbergerRuedi Aebersold
Apr 15, 2017·Acta Neuropathologica·Jik NijssenEva Hedlund
May 5, 2017·Science Translational Medicine·Bradley N SmithChristopher E Shaw
Jul 13, 2017·The New England Journal of Medicine·Robert H Brown, Ammar Al-Chalabi
Mar 24, 2018·Neuron·Aude NicolasJohn E Landers
Oct 24, 2018·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Clarissa BracciaAndrea Armirotti
Oct 24, 2018·Scientific Reports·Tadashi Nakaya, Manolis Maragkakis
Jun 27, 2019·Cell Reports·Riccardo De SantisAlessandro Rosa
Nov 5, 2019·Annals of Clinical and Translational Neurology·Marcel NaumannAndreas Hermann

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Citations

Sep 3, 2021·Communications Biology·Maria Giovanna GaroneAlessandro Rosa

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Methods Mentioned

BETA
FACS
immunoprecipitation
transgenic
PAR-CLIP
RNA-seq
transfection

Software Mentioned

MarkerView
ProteinPilot
DISEASES
SPEC
R package
FIDEA
MASS
R

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