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 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.
1 Division of Metabolism, Department of Paediatrics, University of Zürich, Zürich, Switzerland 2 Affiliated with the Neuroscience Centre Zurich ZNZ, Zürich, Switzerland 3 Affiliated with the Children's Research Centre CRC, Zürich, Switzerland.
Germaine
G
Korner
4 Department of Neurology, University Hospital of Zurich, Zürich, Switzerland.
Daniela
D
Noain
5 Department of Biomedicine, University of Bergen, Bergen, Norway.
Ming
M
Ying
5 Department of Biomedicine, University of Bergen, Bergen, Norway.
Magnus
M
Hole
5 Department of Biomedicine, University of Bergen, Bergen, Norway.
Marte I
MI
Flydal
1 Division of Metabolism, Department of Paediatrics, University of Zürich, Zürich, Switzerland 3 Affiliated with the Children's Research Centre CRC, Zürich, Switzerland.
Tanja
T
Scherer
1 Division of Metabolism, Department of Paediatrics, University of Zürich, Zürich, Switzerland 3 Affiliated with the Children's Research Centre CRC, Zürich, Switzerland.
Gabriella
G
Allegri
6 Division of Clinical Chemistry and Biochemistry, Department of Paediatrics, University of Zürich, Zürich, Switzerland.
Anahita
A
Rassi
7 Swiss Newborn Screening Laboratory, University Children's Hospital, Zurich, Switzerland 3 Affiliated with the Children's Research Centre CRC, Zürich, Switzerland.
Ralph
R
Fingerhut
8 Institute of Biology and Experimental Medicine, Buenos Aires, Argentina.
Damasia
D
Becu-Villalobos
9 Institute of Physiology, University of Zurich, Zürich, Switzerland.
Samyuktha
S
Pillai
3 Affiliated with the Children's Research Centre CRC, Zürich, Switzerland 10 Division of Endocrinology, Department of Pediatrics, University of Zurich, Switzerland.
Stephan
S
Wueest
3 Affiliated with the Children's Research Centre CRC, Zürich, Switzerland 10 Division of Endocrinology, Department of Pediatrics, University of Zurich, Switzerland.
Daniel
D
Konrad
11 Department of Medicine, University of Fribourg, Fribourg, Switzerland.
Anna
A
Lauber-Biason
2 Affiliated with the Neuroscience Centre Zurich ZNZ, Zürich, Switzerland 4 Department of Neurology, University Hospital of Zurich, Zürich, Switzerland.
Christian R
CR
Baumann
12 Department of Clinical Medicine K1, University of Bergen, Norway 13 Department of Neurology, Haukeland University Hospital, Bergen, Norway.
Laurence A
LA
Bindoff
5 Department of Biomedicine, University of Bergen, Bergen, Norway aurora.martinez@biomed.uib.no beat.thony@kispi.uzh.ch.
Aurora
A
Martinez
1 Division of Metabolism, Department of Paediatrics, University of Zürich, Zürich, Switzerland 2 Affiliated with the Neuroscience Centre Zurich ZNZ, Zürich, Switzerland 3 Affiliated with the Children's Research Centre CRC, Zürich, Switzerland aurora.martinez@biomed.uib.no beat.thony@kispi.uzh.ch.
Beat
B
Thöny
D000818:Animals; D001708:Biopterins / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002395:Catecholamines / Q000378:metabolism*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000627:therapeutic use; D004435:Eating / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D055879:Gene Knock-In Techniques; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009069:Movement Disorders / Q000188:drug therapy / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D013974:Thyroxine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism*
D002395:Catecholamines; D015259:Dopamine Agents; D001708:Biopterins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D013974:Thyroxine
catecholamine deficiency; dopamine deficiency; infantile parkinsonism; misfolding; mislocalization