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

Authors
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
Publication Year
2015
Language
English
Format
article
Status
Published version
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.
Fil: Korner, Germaine. Universitat Zurich; Suiza. The Children´s Research Centre; Suiza. Neuroscience Center Zurich; Suiza
Fil: Noain, Daniela. Universitat Zurich; Suiza
Fil: Ying, Ming. University Of Bergen; Noruega
Fil: Hole, Magnus. University Of Bergen; Noruega
Fil: Flydal, Marte I.. University Of Bergen; Noruega
Fil: Scherer, Tanja. Universitat Zurich; Suiza. The Children´s Research Centre;; Suiza
Fil: Allegri, Gabriella. Universitat Zurich; Suiza. The Children´s Research Centre; Suiza
Fil: Rassi, Anahita. Universitat Zurich; Suiza
Fil: Fingerhut, Ralph. University Children´s Hospital; Suiza
Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Pillai, Samyuktha. Universitat Zurich; Suiza
Fil: Wueest, Stephan. The Children’s Research Centre ; Suiza. Universitat Zurich; Suiza
Fil: Konrad, Daniel. Swiss Federal Institute Of Technology Zurich; Suiza
Fil: Lauber Biason, Anna. University of Fribourg; Suiza
Fil: Baumann, Christian R.. Neuroscience Centre Zurich ; Suiza
Fil: Bindoff, Laurence A. University of Fribourg; Suiza
Fil: Martinez, Aurora. University Of Bergen; Noruega
Fil: Beat, Thony. Universitat Zurich; Suiza. Neuroscience Centre Zurich ; Suiza. he Children’s Research Centre ; Suiza
Subject
DOPAMINE
TYROSINE HYDROXYLASE
DYSTONIA
GROWTH HORMONE
INFANTIL PARKINSONISM
Neurociencias
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/8298