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Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation
A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfun...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221533/ https://www.ncbi.nlm.nih.gov/pubmed/21949350 http://dx.doi.org/10.1093/hmg/ddr432 |
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author | Ambegaokar, Surendra S. Jackson, George R. |
author_facet | Ambegaokar, Surendra S. Jackson, George R. |
author_sort | Ambegaokar, Surendra S. |
collection | PubMed |
description | A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfunctional lysosomes, as potent modifiers; here, we report 37 additional genes identified from ∼1900 genes screened, including the kinases shaggy/GSK-3beta, par-1/MARK, CamKI and Mekk1. Tau acts synergistically with Mekk1 and p38 to down-regulate extracellular regulated kinase activity, with a corresponding decrease in AT8 immunoreactivity (pS202/T205), suggesting that tau can participate in signaling pathways to regulate its own kinases. Modifiers showed poor correlation with tau phosphorylation (using the AT8, 12E8 and AT270 epitopes); moreover, tested suppressors of wild-type tau were equally effective in suppressing toxicity of a phosphorylation-resistant S11A tau construct, demonstrating that changes in tau phosphorylation state are not required to suppress or enhance its toxicity. Genes related to autophagy, the cell cycle, RNA-associated proteins and chromatin-binding proteins constitute a large percentage of identified modifiers. Other functional categories identified include mitochondrial proteins, lipid trafficking, Golgi proteins, kinesins and dynein and the Hsp70/Hsp90-organizing protein (Hop). Network analysis uncovered several other genes highly associated with the functional modifiers, including genes related to the PI3K, Notch, BMP/TGF-β and Hedgehog pathways, and nuclear trafficking. Activity of GSK-3β is strongly upregulated due to TDP-43 expression, and reduced GSK-3β dosage is also a common suppressor of Aβ42 and TDP-43 toxicity. These findings suggest therapeutic targets other than mitigation of tau phosphorylation. |
format | Online Article Text |
id | pubmed-3221533 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-32215332011-11-21 Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation Ambegaokar, Surendra S. Jackson, George R. Hum Mol Genet Articles A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfunctional lysosomes, as potent modifiers; here, we report 37 additional genes identified from ∼1900 genes screened, including the kinases shaggy/GSK-3beta, par-1/MARK, CamKI and Mekk1. Tau acts synergistically with Mekk1 and p38 to down-regulate extracellular regulated kinase activity, with a corresponding decrease in AT8 immunoreactivity (pS202/T205), suggesting that tau can participate in signaling pathways to regulate its own kinases. Modifiers showed poor correlation with tau phosphorylation (using the AT8, 12E8 and AT270 epitopes); moreover, tested suppressors of wild-type tau were equally effective in suppressing toxicity of a phosphorylation-resistant S11A tau construct, demonstrating that changes in tau phosphorylation state are not required to suppress or enhance its toxicity. Genes related to autophagy, the cell cycle, RNA-associated proteins and chromatin-binding proteins constitute a large percentage of identified modifiers. Other functional categories identified include mitochondrial proteins, lipid trafficking, Golgi proteins, kinesins and dynein and the Hsp70/Hsp90-organizing protein (Hop). Network analysis uncovered several other genes highly associated with the functional modifiers, including genes related to the PI3K, Notch, BMP/TGF-β and Hedgehog pathways, and nuclear trafficking. Activity of GSK-3β is strongly upregulated due to TDP-43 expression, and reduced GSK-3β dosage is also a common suppressor of Aβ42 and TDP-43 toxicity. These findings suggest therapeutic targets other than mitigation of tau phosphorylation. Oxford University Press 2011-12-15 2011-09-23 /pmc/articles/PMC3221533/ /pubmed/21949350 http://dx.doi.org/10.1093/hmg/ddr432 Text en © The Author 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Ambegaokar, Surendra S. Jackson, George R. Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation |
title | Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation |
title_full | Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation |
title_fullStr | Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation |
title_full_unstemmed | Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation |
title_short | Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation |
title_sort | functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221533/ https://www.ncbi.nlm.nih.gov/pubmed/21949350 http://dx.doi.org/10.1093/hmg/ddr432 |
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