Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models

Summary: Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the...

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Autores principales:	Anny Devoy, Georgia Price, Francesca De Giorgio, Rosie Bunton-Stasyshyn, David Thompson, Samanta Gasco, Alasdair Allan, Gemma F. Codner, Remya R. Nair, Charlotte Tibbit, Ross McLeod, Zeinab Ali, Judith Noda, Alessandro Marrero-Gagliardi, José M. Brito-Armas, Muhammet M. Öztürk, Michelle Simon, Edward O'Neill, Sam Bryce-Smith, Jackie Harrison, Gemma Atkins, Silvia Corrochano, Michelle Stewart, Lydia Teboul, Abraham Acevedo-Arozena, Elizabeth M.C. Fisher, Thomas J. Cunningham
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Neurogenetics Neuroscience Model organism Science Q
Acceso en línea:	https://doaj.org/article/5af44f859e954ddaba09b5e693fc05a6
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spelling	oai:doaj.org-article:5af44f859e954ddaba09b5e693fc05a62021-11-28T04:36:56ZGeneration and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models2589-004210.1016/j.isci.2021.103463https://doaj.org/article/5af44f859e954ddaba09b5e693fc05a62021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221014346https://doaj.org/toc/2589-0042Summary: Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context.Anny DevoyGeorgia PriceFrancesca De GiorgioRosie Bunton-StasyshynDavid ThompsonSamanta GascoAlasdair AllanGemma F. CodnerRemya R. NairCharlotte TibbitRoss McLeodZeinab AliJudith NodaAlessandro Marrero-GagliardiJosé M. Brito-ArmasMuhammet M. ÖztürkMichelle SimonEdward O'NeillSam Bryce-SmithJackie HarrisonGemma AtkinsSilvia CorrochanoMichelle StewartLydia TeboulAbraham Acevedo-ArozenaElizabeth M.C. FisherThomas J. CunninghamElsevierarticleNeurogeneticsNeuroscienceModel organismScienceQENiScience, Vol 24, Iss 12, Pp 103463- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurogenetics Neuroscience Model organism Science Q
spellingShingle	Neurogenetics Neuroscience Model organism Science Q Anny Devoy Georgia Price Francesca De Giorgio Rosie Bunton-Stasyshyn David Thompson Samanta Gasco Alasdair Allan Gemma F. Codner Remya R. Nair Charlotte Tibbit Ross McLeod Zeinab Ali Judith Noda Alessandro Marrero-Gagliardi José M. Brito-Armas Muhammet M. Öztürk Michelle Simon Edward O'Neill Sam Bryce-Smith Jackie Harrison Gemma Atkins Silvia Corrochano Michelle Stewart Lydia Teboul Abraham Acevedo-Arozena Elizabeth M.C. Fisher Thomas J. Cunningham Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models
description	Summary: Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context.
format	article
author	Anny Devoy Georgia Price Francesca De Giorgio Rosie Bunton-Stasyshyn David Thompson Samanta Gasco Alasdair Allan Gemma F. Codner Remya R. Nair Charlotte Tibbit Ross McLeod Zeinab Ali Judith Noda Alessandro Marrero-Gagliardi José M. Brito-Armas Muhammet M. Öztürk Michelle Simon Edward O'Neill Sam Bryce-Smith Jackie Harrison Gemma Atkins Silvia Corrochano Michelle Stewart Lydia Teboul Abraham Acevedo-Arozena Elizabeth M.C. Fisher Thomas J. Cunningham
author_facet	Anny Devoy Georgia Price Francesca De Giorgio Rosie Bunton-Stasyshyn David Thompson Samanta Gasco Alasdair Allan Gemma F. Codner Remya R. Nair Charlotte Tibbit Ross McLeod Zeinab Ali Judith Noda Alessandro Marrero-Gagliardi José M. Brito-Armas Muhammet M. Öztürk Michelle Simon Edward O'Neill Sam Bryce-Smith Jackie Harrison Gemma Atkins Silvia Corrochano Michelle Stewart Lydia Teboul Abraham Acevedo-Arozena Elizabeth M.C. Fisher Thomas J. Cunningham
author_sort	Anny Devoy
title	Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models
title_short	Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models
title_full	Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models
title_fullStr	Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models
title_full_unstemmed	Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models
title_sort	generation and analysis of innovative genomically humanized knockin sod1, tardbp (tdp-43), and fus mouse models
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/5af44f859e954ddaba09b5e693fc05a6
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Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models

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