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

Abstract

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.

• Authors: Germaine Korner, Daniela Noain, Ming Ying, Magnus Hole, Marte I Flydal, Tanja Scherer, Gabriella Allegri, Anahita Rassi, Ralph Fingerhut, Damasia Becu-Villalobos, Samyuktha Pillai, Stephan Wueest, Daniel Konrad, Anna Lauber-Biason, Christian R Baumann, Laurence A Bindoff, Aurora Martinez, Beat Thöny
• Journal: Brain : a journal of neurology (Brain) Vol. 138 Issue Pt 10 Pg. 2948-63 (Oct 2015) ISSN: 1460-2156 [Electronic] England
• PMID: 26276013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Catecholamines
• Dopamine Agents
• Biopterins
• Levodopa
• Tyrosine 3-Monooxygenase
• Thyroxine

Topics

• Animals
• Biopterins (metabolism)
• Brain (metabolism, pathology)
• Catecholamines (metabolism)
• Disease Models, Animal
• Dopamine Agents (therapeutic use)
• Eating (genetics)
• Female
• Gene Expression Regulation (genetics)
• Gene Knock-In Techniques
• Levodopa (therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Motor Activity (genetics)
• Movement Disorders (drug therapy, pathology)
• Mutation (genetics)
• Thyroxine (metabolism)
• Tyrosine 3-Monooxygenase (genetics, metabolism)