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

KORNER, GERMAINE; NOAIN, DANIELA; YING, MING; HOLE, MAGNUS; FLYDAL, MARTE I; SCHERER, TANJA; ALLEGRI, GABRIELLA; RASSI, ANAHITA; FINGERHUT, RALPH; BECU VILLALOBOS, DAMASIA; PILLAI, SAMYUKTHA; WUEEST, STEPHAN; KONRAD, DANIEL; LAUBER-BIASON, ANNA; BAUMANN,CHRISTIAN R.; BINDOFF, LAURENCE A; MARTINEZ, AURORA; BEAT, THONY

BRAIN

OXFORD UNIV PRESS

Lugar: Oxford; Año: 2015 vol. 138 p. 2948 - 2963

0006-8950

-----Original Message-----From: onbehalfof+brain+ucl.ac.uk@manuscriptcentral.com [mailto:onbehalfof+brain+ucl.ac.uk@manuscriptcentral.com] On Behalf Of brain@ucl.ac.ukSent: Wednesday, June 17, 2015 6:33 PMTo: Thöny, BeatSubject: Brain - Decision on Manuscript ID BRAIN-2015-00246.R2BRAIN-2015-00246.R2Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiencyDear Dr Thony,We are pleased to let you know that your paper has now been accepted for publication in Brain.PROOFS - You will receive pdf proofs from Oxford Journals by email in due course. The article will be copy-edited, but responsibility for the version that ultimately is published lies with the authors. Please therefore check the proofs carefully and mark all changes clearly. We ask that proofs be returned to Oxford Journals within two days of receipt. If you anticipate not being available to check the proofs, please email brain@ucl.ac.uk to nominate another author to whom the proofs should be sent.COVER ART AND TWITTER FEED - We would be grateful for suggestions for cover art and images for our Twitter feed, based on the content of your paper. Please also include a detailed legend with your cover art proposal.VIDEO ABSTRACT - The Brain website hosts a limited number of video abstracts to accompany each issue. If you are interested in producing a 5-min video abstract to promote your manuscript, then please contact the Editorial Office (brain@ucl.ac.uk) for further details and guidelines.OPTIONAL OPEN ACCESS - Brain authors can opt to make their paper freely available online to all immediately upon publication as part of the Oxford Open initiative. Applicable Open Access charges can be found at http://www.oxfordjournals.org/oxfordopen. This option can be taken up with Oxford Journals by contacting brainj@oup.com after you have received your proofs.PRESS RELEASES - The OUP publicity team can issue press releases on newsworthy articles. If you or your institution intend to issue a press release on this article, please inform the Editorial Office (brain@ucl.ac.uk) to arrange an embargo date for the publication of the paper.Thank you for your submitting this interesting paper to Brain. We hope you will consider submitting additional work of the same quality in the future.Yours sincerely,Andy SingletonAssociate EditorDimitri KullmannEditorTyrosine hydroxylase catalyzes 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 Doparesponsive 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 miceshowed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-based gate and catalepsy. This phenotype was associated to 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 tyrosinehydroxylase 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 hydroxylaseprotein 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 formovement disorders with loss of dopaminergic input to the striatum.