Abstract
Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine synthesis. Two clinical phenotypes have been described. The THD “B” phenotype produces a severe encephalopathy of early-onset with sub-optimal L-Dopa response, whereas the “A” phenotype has a better L-Dopa response and outcome. The objective of the study is to describe the expression of key synaptic proteins and neurodevelopmental markers in a fetal brain of THD “B” phenotype. The brain of a 16-week-old miscarried human fetus was dissected in different brain areas and frozen until the analysis. TH gene study revealed the p.R328W/p.T399M mutations, the same mutations that produced a B phenotype in her sister. After protein extraction, western blot analyses were performed to assess protein expression. The results were compared to an age-matched control. We observed a decreased expression in TH and in other dopaminergic proteins, such as VMAT 1 and 2 and dopamine receptors, especially D2DR. GABAergic and glutamatergic proteins such as GABA VT, NMDAR1 and calbindin were also altered. Developmental markers for synapses, axons and dendrites were decreased whereas markers of neuronal volume were preserved. Although this is an isolated case, this brain sample is unique and corresponds to the first reported study of a THD brain. It provides interesting information about the influence of dopamine as a regulator of other neurotransmitter systems, brain development and movement disorders with origin at the embryological state. This study could also contribute to a better understanding of the pathophysiology of THD at early fetal stages.
References
Althini S, Bengtsson H, Usoskin D et al (2003) Normal nigrostriatal innervation but dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase. J Neurosci Res 72:444–53
Belinsky GS, Sirois CL, Rich MT et al (2013) Dopamine receptors in human embryonic stem cell neurodifferentiation. Stem Cells Dev 22(10):1522–40
Iravani MM, McCreary AC, Jenner P (2012) Striatal plasticity in Parkinson’s disease and L-dopa induced dyskinesia. Parkinsonism Relat Disord 18(Suppl 1):S123–5
Kobayashi K, Morita S, Sawada H et al (1995) Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice. J Biol Chem 270(45):27235–43
Korner G, Noain D, Ying M, Hole M, Flydal MI, Scherer T, Allegri G et al (2015) Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency. Brain 138(Pt 10):2948–63
Møller LB, Romstad A, Paulsen M et al (2005) Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency. Prenat Diagn 25(8):671–5
Money KM, Stanwood GD (2013) Developmental origins of brain disorders: roles for dopamine. Front Cell Neurosci 7:260
Prakash N, Wurst W (2006) Development of dopaminergic neurons in the mammalian brain. Cell Mol Life Sci 63(2):187–206
Tokuoka H, Muramatsu S, Sumi-Ichinose C et al (2011) Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection. J Biol Chem 286(50):43549–58
Tristsch N, Ding J, Sabatini B (2012) Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature 490(7419):262–66
Tsui A, Isacson O (2011) Functions of the nigrostriatal dopaminergic synapse and the use of neurotransplantation in Parkinson’s disease. J Neurol 258(8):1393–405
Willemsen MA, Verbeek MM, Kamsteeg E-J et al (2010) Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain 133(6):1810–22
Zeiss CJ (2005) Neuroanatomical phenotyping in the mouse: the dopaminergic system. Vet Pathol 42(6):753–73
Zhou Q-Y, Palmiter RD (1995) Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83(7):1197–209
Zhou Q, Quaife C, Palmitter R (1995) Targeted disruption of the tyrosine hydroxylase gene reveals that cathecolamines are required for mouse fetal development. Nature 374(6523):640–3
Acknowledgments
Dr. AGC is funded by the project PS09/01132 ISCIII-FEDER. ATN was initially funded by a grant from the “Fundación Godía” and later on by PFIS grant.
We thank the participating family for their collaboration with this study. We thank Carles Lerín and Núria Villamanzo for their generously supplying of the Bullet Blender System and their assistance.
This study was funded by the project PS09/01132 ISCIII-FEDER.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Tristán-Noguero, A., Díez, H., Jou, C. et al. Study of a fetal brain affected by a severe form of tyrosine hydroxylase deficiency, a rare cause of early parkinsonism. Metab Brain Dis 31, 705–709 (2016). https://doi.org/10.1007/s11011-015-9780-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-015-9780-z