A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia

Cytoplasmic aggregation of Tar-DNA/RNA binding protein 43 (TDP-43) occurs in 97 percent of amyotrophic lateral sclerosis (ALS), ~40% of frontotemporal dementia (FTD) and in many cases of Alzheimer’s disease (AD). Cytoplasmic TDP-43 inclusions are seen in both sporadic and familial forms of these dis...

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Autores principales:	Jorge Azpurua, Enas Gad El-Karim, Marvel Tranquille, Josh Dubnau
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/aa3c4614bf9e4f30bae6ff78422d4ae3
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spelling	oai:doaj.org-article:aa3c4614bf9e4f30bae6ff78422d4ae32021-11-18T06:15:48ZA behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia1553-73901553-7404https://doaj.org/article/aa3c4614bf9e4f30bae6ff78422d4ae32021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584670/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Cytoplasmic aggregation of Tar-DNA/RNA binding protein 43 (TDP-43) occurs in 97 percent of amyotrophic lateral sclerosis (ALS), ~40% of frontotemporal dementia (FTD) and in many cases of Alzheimer’s disease (AD). Cytoplasmic TDP-43 inclusions are seen in both sporadic and familial forms of these disorders, including those cases that are caused by repeat expansion mutations in the C9orf72 gene. To identify downstream mediators of TDP-43 toxicity, we expressed human TDP-43 in a subset of Drosophila motor neurons. Such expression causes age-dependent deficits in negative geotaxis behavior. Using this behavioral readout of locomotion, we conducted an shRNA suppressor screen and identified 32 transcripts whose knockdown was sufficient to ameliorate the neurological phenotype. The majority of these suppressors also substantially suppressed the negative effects on lifespan seen with glial TDP-43 expression. In addition to identification of a number of genes whose roles in neurodegeneration were not previously known, our screen also yielded genes involved in chromatin regulation and nuclear/import export- pathways that were previously identified in the context of cell based or neurodevelopmental suppressor screens. A notable example is SF2, a conserved orthologue of mammalian SRSF1, an RNA binding protein with roles in splicing and nuclear export. Our identification SF2/SRSF1 as a potent suppressor of both neuronal and glial TDP-43 toxicity also provides a convergence with C9orf72 expansion repeat mediated neurodegeneration, where this gene also acts as a downstream mediator. Author summary Loss of nuclear function of TDP-43 and its mislocalization into cytoplasmic inclusions are central features to a suite of neurodegenerative disorders. We screened 2700 Drosophila genes to identify downstream mediators that suppress an age-dependent motor dysfunction phenotype when they are knocked down by RNA interference. We identified both previously implicated pathways and several novel genes whose knock down is sufficient to dramatically and robustly rescue TDP-43 toxicity both in neuronal and glial contexts. Notably, we demonstrate that SF2/SRSF1, which was previously reported as a suppressor of C9orf72 hexanucleotide expansion repeat toxicity, also is a potent suppressor of TDP-43 mediated neurodegeneration.Jorge AzpuruaEnas Gad El-KarimMarvel TranquilleJosh DubnauPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Jorge Azpurua Enas Gad El-Karim Marvel Tranquille Josh Dubnau A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia
description	Cytoplasmic aggregation of Tar-DNA/RNA binding protein 43 (TDP-43) occurs in 97 percent of amyotrophic lateral sclerosis (ALS), ~40% of frontotemporal dementia (FTD) and in many cases of Alzheimer’s disease (AD). Cytoplasmic TDP-43 inclusions are seen in both sporadic and familial forms of these disorders, including those cases that are caused by repeat expansion mutations in the C9orf72 gene. To identify downstream mediators of TDP-43 toxicity, we expressed human TDP-43 in a subset of Drosophila motor neurons. Such expression causes age-dependent deficits in negative geotaxis behavior. Using this behavioral readout of locomotion, we conducted an shRNA suppressor screen and identified 32 transcripts whose knockdown was sufficient to ameliorate the neurological phenotype. The majority of these suppressors also substantially suppressed the negative effects on lifespan seen with glial TDP-43 expression. In addition to identification of a number of genes whose roles in neurodegeneration were not previously known, our screen also yielded genes involved in chromatin regulation and nuclear/import export- pathways that were previously identified in the context of cell based or neurodevelopmental suppressor screens. A notable example is SF2, a conserved orthologue of mammalian SRSF1, an RNA binding protein with roles in splicing and nuclear export. Our identification SF2/SRSF1 as a potent suppressor of both neuronal and glial TDP-43 toxicity also provides a convergence with C9orf72 expansion repeat mediated neurodegeneration, where this gene also acts as a downstream mediator. Author summary Loss of nuclear function of TDP-43 and its mislocalization into cytoplasmic inclusions are central features to a suite of neurodegenerative disorders. We screened 2700 Drosophila genes to identify downstream mediators that suppress an age-dependent motor dysfunction phenotype when they are knocked down by RNA interference. We identified both previously implicated pathways and several novel genes whose knock down is sufficient to dramatically and robustly rescue TDP-43 toxicity both in neuronal and glial contexts. Notably, we demonstrate that SF2/SRSF1, which was previously reported as a suppressor of C9orf72 hexanucleotide expansion repeat toxicity, also is a potent suppressor of TDP-43 mediated neurodegeneration.
format	article
author	Jorge Azpurua Enas Gad El-Karim Marvel Tranquille Josh Dubnau
author_facet	Jorge Azpurua Enas Gad El-Karim Marvel Tranquille Josh Dubnau
author_sort	Jorge Azpurua
title	A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia
title_short	A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia
title_full	A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia
title_fullStr	A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia
title_full_unstemmed	A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia
title_sort	behavioral screen for mediators of age-dependent tdp-43 neurodegeneration identifies sf2/srsf1 among a group of potent suppressors in both neurons and glia
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/aa3c4614bf9e4f30bae6ff78422d4ae3
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A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia

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