Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency

Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes...

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Autores: Korner, Germaine, Noain, Daniela, Ying, Ming, Hole, Magnus, Flydal, Marte I., Scherer, Tanja, Allegri, Gabriella, Rassi, Anahita, Fingerhut, Ralph, Becu, Damasia, Pillai, Samyuktha, Wueest, Stephan, Konrad, Daniel, Lauber Biason, Anna, Baumann, Christian R., Bindoff, Laurence A, Martinez, Aurora, Beat, Thony
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/8298
Acceso en línea:http://hdl.handle.net/11336/8298
Access Level:acceso abierto
Palabra clave:Dopamine
Tyrosine Hydroxylase
Dystonia
Growth Hormone
Infantil Parkinsonism
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
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oai_identifier_str oai:ri.conicet.gov.ar:11336/8298
network_acronym_str AR
network_name_str Argentina
repository_id_str
dc.title.none.fl_str_mv Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency
title Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency
spellingShingle Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency
Korner, Germaine
Dopamine
Tyrosine Hydroxylase
Dystonia
Growth Hormone
Infantil Parkinsonism
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
title_short Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency
title_full Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency
title_fullStr Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency
title_full_unstemmed Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency
title_sort Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency
dc.creator.none.fl_str_mv Korner, Germaine
Noain, Daniela
Ying, Ming
Hole, Magnus
Flydal, Marte I.
Scherer, Tanja
Allegri, Gabriella
Rassi, Anahita
Fingerhut, Ralph
Becu, Damasia
Pillai, Samyuktha
Wueest, Stephan
Konrad, Daniel
Lauber Biason, Anna
Baumann, Christian R.
Bindoff, Laurence A
Martinez, Aurora
Beat, Thony
author Korner, Germaine
author_facet Korner, Germaine
Noain, Daniela
Ying, Ming
Hole, Magnus
Flydal, Marte I.
Scherer, Tanja
Allegri, Gabriella
Rassi, Anahita
Fingerhut, Ralph
Becu, Damasia
Pillai, Samyuktha
Wueest, Stephan
Konrad, Daniel
Lauber Biason, Anna
Baumann, Christian R.
Bindoff, Laurence A
Martinez, Aurora
Beat, Thony
author_role author
author2 Noain, Daniela
Ying, Ming
Hole, Magnus
Flydal, Marte I.
Scherer, Tanja
Allegri, Gabriella
Rassi, Anahita
Fingerhut, Ralph
Becu, Damasia
Pillai, Samyuktha
Wueest, Stephan
Konrad, Daniel
Lauber Biason, Anna
Baumann, Christian R.
Bindoff, Laurence A
Martinez, Aurora
Beat, Thony
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Dopamine
Tyrosine Hydroxylase
Dystonia
Growth Hormone
Infantil Parkinsonism
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
topic Dopamine
Tyrosine Hydroxylase
Dystonia
Growth Hormone
Infantil Parkinsonism
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
description Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and DOPA-responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th knock-in mice with the mutation Th-p.R203H, equivalent to the most recurrent human mutation associated with type B tyrosine hydroxylase deficiency (TH-p.R233H), often unresponsive to l-DOPA treatment. The Th knock-in mice showed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-based gate and catalepsy. This phenotype was associated with a gradual loss of central catecholamines and the serious manifestations of motor impairment presented diurnal fluctuation but did not improve with standard l-DOPA treatment. The mutant tyrosine hydroxylase enzyme was unstable and exhibited deficient stabilization by catecholamines, leading to decline of brain tyrosine hydroxylase-immunoreactivity in the Th knock-in mice. In fact the substantia nigra presented an almost normal level of mutant tyrosine hydroxylase protein but distinct absence of the enzyme was observed in the striatum, indicating a mutation-associated mislocalization of tyrosine hydroxylase in the nigrostriatal pathway. This hypomorphic mouse model thus provides understanding on pathomechanisms in type B tyrosine hydroxylase deficiency and a platform for the evaluation of novel therapeutics for movement disorders with loss of dopaminergic input to the striatum.
publishDate 2015
dc.date.none.fl_str_mv 2015-08-14
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/11336/8298
Korner, Germaine; Noain, Daniela; Ying, Ming; Hole, Magnus; Flydal, Marte I.; et al.; Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency; Oxford University Press; Brain; 138; 10; 14-8-2015; 2948-2963
0006-8950
1460-2156
url http://hdl.handle.net/11336/8298
identifier_str_mv Korner, Germaine; Noain, Daniela; Ying, Ming; Hole, Magnus; Flydal, Marte I.; et al.; Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency; Oxford University Press; Brain; 138; 10; 14-8-2015; 2948-2963
0006-8950
1460-2156
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1093/brain/awv224
info:eu-repo/semantics/altIdentifier/url/http://brain.oxfordjournals.org/content/138/10/2948.long
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
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
_version_ 1799195045044158464
spelling Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiencyKorner, GermaineNoain, DanielaYing, MingHole, MagnusFlydal, Marte I.Scherer, TanjaAllegri, GabriellaRassi, AnahitaFingerhut, RalphBecu, DamasiaPillai, SamyukthaWueest, StephanKonrad, DanielLauber Biason, AnnaBaumann, Christian R.Bindoff, Laurence AMartinez, AuroraBeat, ThonyDopamineTyrosine HydroxylaseDystoniaGrowth HormoneInfantil Parkinsonismhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and DOPA-responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th knock-in mice with the mutation Th-p.R203H, equivalent to the most recurrent human mutation associated with type B tyrosine hydroxylase deficiency (TH-p.R233H), often unresponsive to l-DOPA treatment. The Th knock-in mice showed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-based gate and catalepsy. This phenotype was associated with a gradual loss of central catecholamines and the serious manifestations of motor impairment presented diurnal fluctuation but did not improve with standard l-DOPA treatment. The mutant tyrosine hydroxylase enzyme was unstable and exhibited deficient stabilization by catecholamines, leading to decline of brain tyrosine hydroxylase-immunoreactivity in the Th knock-in mice. In fact the substantia nigra presented an almost normal level of mutant tyrosine hydroxylase protein but distinct absence of the enzyme was observed in the striatum, indicating a mutation-associated mislocalization of tyrosine hydroxylase in the nigrostriatal pathway. This hypomorphic mouse model thus provides understanding on pathomechanisms in type B tyrosine hydroxylase deficiency and a platform for the evaluation of novel therapeutics for movement disorders with loss of dopaminergic input to the striatum.Fil: Korner, Germaine. Universitat Zurich; Suiza. The Children´s Research Centre; Suiza. Neuroscience Center Zurich; SuizaFil: Noain, Daniela. Universitat Zurich; SuizaFil: Ying, Ming. University Of Bergen; NoruegaFil: Hole, Magnus. University Of Bergen; NoruegaFil: Flydal, Marte I.. University Of Bergen; NoruegaFil: Scherer, Tanja. Universitat Zurich; Suiza. The Children´s Research Centre;; SuizaFil: Allegri, Gabriella. Universitat Zurich; Suiza. The Children´s Research Centre; SuizaFil: Rassi, Anahita. Universitat Zurich; SuizaFil: Fingerhut, Ralph. University Children´s Hospital; SuizaFil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Pillai, Samyuktha. Universitat Zurich; SuizaFil: Wueest, Stephan. The Children’s Research Centre ; Suiza. Universitat Zurich; SuizaFil: Konrad, Daniel. Swiss Federal Institute Of Technology Zurich; SuizaFil: Lauber Biason, Anna. University of Fribourg; SuizaFil: Baumann, Christian R.. Neuroscience Centre Zurich ; SuizaFil: Bindoff, Laurence A. University of Fribourg; SuizaFil: Martinez, Aurora. University Of Bergen; NoruegaFil: Beat, Thony. Universitat Zurich; Suiza. Neuroscience Centre Zurich ; Suiza. he Children’s Research Centre ; SuizaOxford University Press2015-08-14info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/8298Korner, Germaine; Noain, Daniela; Ying, Ming; Hole, Magnus; Flydal, Marte I.; et al.; Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency; Oxford University Press; Brain; 138; 10; 14-8-2015; 2948-29630006-89501460-2156enginfo:eu-repo/semantics/altIdentifier/doi/10.1093/brain/awv224info:eu-repo/semantics/altIdentifier/url/http://brain.oxfordjournals.org/content/138/10/2948.longinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2024-05-08T13:42:09Zoai:ri.conicet.gov.ar:11336/8298instacron: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:34982024-05-08 13:42:09.887CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
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