WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12

Autores
Hussain, Tabish; Sanchez, Kevin; Crayton, Jennifer; Saha, Dhurjhoti; Jeter, Collene; Lu, Yue; Abba, Martín Carlos; Seo, Ryan; Noebels, Jeffrey L.; Fonken, Laura; Aldaz, C. Marcelo
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12, MIM:614322). This mutation affecting the WW1 protein binding domain of WWOX, impairs its interaction with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T mutation that phenocopies human SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination, and unlike KO models that survive only for 1 month, live beyond 1 year of age. These deficits progressed with age and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice brains revealed signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. Cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions of WW domain LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation, and severe cerebellar dysfunction. Our results show significant pathobiological effects and potential mechanisms through which WWOX partial LoF leads to epilepsy, cerebellar neurodegeneration, neuroinflammation, and ataxia. Additionally, the mouse model described here will be a useful tool to understand the role of WWOX in common neurodegenerative conditions in which this gene has been identified as a novel risk factor.
Fil: Hussain, Tabish. University of Texas; Estados Unidos
Fil: Sanchez, Kevin. University of Texas at Austin; Estados Unidos
Fil: Crayton, Jennifer. University of Texas; Estados Unidos
Fil: Saha, Dhurjhoti. University of Texas; Estados Unidos
Fil: Jeter, Collene. University of Texas; Estados Unidos
Fil: Lu, Yue. University of Texas; Estados Unidos
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Seo, Ryan. Baylor College of Medicine; Estados Unidos
Fil: Noebels, Jeffrey L.. Baylor College of Medicine; Estados Unidos
Fil: Fonken, Laura. University of Texas at Austin; Estados Unidos
Fil: Aldaz, C. Marcelo. University of Texas; Estados Unidos
Materia
ATAXIA
EPILEPSY
NEURODEGENERATION
NEUROINFLAMMATION
SCAR12
WWOX
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/222969
Acceder
id CONICETDig_1f3d2cb1978bb311141cdd55bd9176ca
oai_identifier_str oai:ri.conicet.gov.ar:11336/222969
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12Hussain, TabishSanchez, KevinCrayton, JenniferSaha, DhurjhotiJeter, ColleneLu, YueAbba, Martín CarlosSeo, RyanNoebels, Jeffrey L.Fonken, LauraAldaz, C. MarceloATAXIAEPILEPSYNEURODEGENERATIONNEUROINFLAMMATIONSCAR12WWOXhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12, MIM:614322). This mutation affecting the WW1 protein binding domain of WWOX, impairs its interaction with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T mutation that phenocopies human SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination, and unlike KO models that survive only for 1 month, live beyond 1 year of age. These deficits progressed with age and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice brains revealed signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. Cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions of WW domain LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation, and severe cerebellar dysfunction. Our results show significant pathobiological effects and potential mechanisms through which WWOX partial LoF leads to epilepsy, cerebellar neurodegeneration, neuroinflammation, and ataxia. Additionally, the mouse model described here will be a useful tool to understand the role of WWOX in common neurodegenerative conditions in which this gene has been identified as a novel risk factor.Fil: Hussain, Tabish. University of Texas; Estados UnidosFil: Sanchez, Kevin. University of Texas at Austin; Estados UnidosFil: Crayton, Jennifer. University of Texas; Estados UnidosFil: Saha, Dhurjhoti. University of Texas; Estados UnidosFil: Jeter, Collene. University of Texas; Estados UnidosFil: Lu, Yue. University of Texas; Estados UnidosFil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Seo, Ryan. Baylor College of Medicine; Estados UnidosFil: Noebels, Jeffrey L.. Baylor College of Medicine; Estados UnidosFil: Fonken, Laura. University of Texas at Austin; Estados UnidosFil: Aldaz, C. Marcelo. University of Texas; Estados UnidosPergamon-Elsevier Science Ltd2023-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/222969Hussain, Tabish; Sanchez, Kevin; Crayton, Jennifer; Saha, Dhurjhoti; Jeter, Collene; et al.; WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12; Pergamon-Elsevier Science Ltd; Progress In Neurobiology; 223; 4-2023; 1-190301-0082CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.pneurobio.2023.102425info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:07:19Zoai:ri.conicet.gov.ar:11336/222969instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:07:20.157CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
title WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
spellingShingle WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
Hussain, Tabish
ATAXIA
EPILEPSY
NEURODEGENERATION
NEUROINFLAMMATION
SCAR12
WWOX
title_short WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
title_full WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
title_fullStr WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
title_full_unstemmed WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
title_sort WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
dc.creator.none.fl_str_mv Hussain, Tabish
Sanchez, Kevin
Crayton, Jennifer
Saha, Dhurjhoti
Jeter, Collene
Lu, Yue
Abba, Martín Carlos
Seo, Ryan
Noebels, Jeffrey L.
Fonken, Laura
Aldaz, C. Marcelo
author Hussain, Tabish
author_facet Hussain, Tabish
Sanchez, Kevin
Crayton, Jennifer
Saha, Dhurjhoti
Jeter, Collene
Lu, Yue
Abba, Martín Carlos
Seo, Ryan
Noebels, Jeffrey L.
Fonken, Laura
Aldaz, C. Marcelo
author_role author
author2 Sanchez, Kevin
Crayton, Jennifer
Saha, Dhurjhoti
Jeter, Collene
Lu, Yue
Abba, Martín Carlos
Seo, Ryan
Noebels, Jeffrey L.
Fonken, Laura
Aldaz, C. Marcelo
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ATAXIA
EPILEPSY
NEURODEGENERATION
NEUROINFLAMMATION
SCAR12
WWOX
topic ATAXIA
EPILEPSY
NEURODEGENERATION
NEUROINFLAMMATION
SCAR12
WWOX
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12, MIM:614322). This mutation affecting the WW1 protein binding domain of WWOX, impairs its interaction with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T mutation that phenocopies human SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination, and unlike KO models that survive only for 1 month, live beyond 1 year of age. These deficits progressed with age and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice brains revealed signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. Cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions of WW domain LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation, and severe cerebellar dysfunction. Our results show significant pathobiological effects and potential mechanisms through which WWOX partial LoF leads to epilepsy, cerebellar neurodegeneration, neuroinflammation, and ataxia. Additionally, the mouse model described here will be a useful tool to understand the role of WWOX in common neurodegenerative conditions in which this gene has been identified as a novel risk factor.
Fil: Hussain, Tabish. University of Texas; Estados Unidos
Fil: Sanchez, Kevin. University of Texas at Austin; Estados Unidos
Fil: Crayton, Jennifer. University of Texas; Estados Unidos
Fil: Saha, Dhurjhoti. University of Texas; Estados Unidos
Fil: Jeter, Collene. University of Texas; Estados Unidos
Fil: Lu, Yue. University of Texas; Estados Unidos
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Seo, Ryan. Baylor College of Medicine; Estados Unidos
Fil: Noebels, Jeffrey L.. Baylor College of Medicine; Estados Unidos
Fil: Fonken, Laura. University of Texas at Austin; Estados Unidos
Fil: Aldaz, C. Marcelo. University of Texas; Estados Unidos
description WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12, MIM:614322). This mutation affecting the WW1 protein binding domain of WWOX, impairs its interaction with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T mutation that phenocopies human SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination, and unlike KO models that survive only for 1 month, live beyond 1 year of age. These deficits progressed with age and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice brains revealed signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. Cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions of WW domain LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation, and severe cerebellar dysfunction. Our results show significant pathobiological effects and potential mechanisms through which WWOX partial LoF leads to epilepsy, cerebellar neurodegeneration, neuroinflammation, and ataxia. Additionally, the mouse model described here will be a useful tool to understand the role of WWOX in common neurodegenerative conditions in which this gene has been identified as a novel risk factor.
publishDate 2023
dc.date.none.fl_str_mv 2023-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/222969
Hussain, Tabish; Sanchez, Kevin; Crayton, Jennifer; Saha, Dhurjhoti; Jeter, Collene; et al.; WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12; Pergamon-Elsevier Science Ltd; Progress In Neurobiology; 223; 4-2023; 1-19
0301-0082
CONICET Digital
CONICET
url http://hdl.handle.net/11336/222969
identifier_str_mv Hussain, Tabish; Sanchez, Kevin; Crayton, Jennifer; Saha, Dhurjhoti; Jeter, Collene; et al.; WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12; Pergamon-Elsevier Science Ltd; Progress In Neurobiology; 223; 4-2023; 1-19
0301-0082
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.pneurobio.2023.102425
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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