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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/222969
Ver los metadatos del registro completo
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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 Técnicas2025-09-29T10:10:06Zoai: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:34982025-09-29 10:10:07.094CONICET 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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1844613987047571456 |
score |
13.070432 |