Aromatic L-amino acid decarboxylase (AADC) is crucial for brain development and motor functions.
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric neuro-metabolic disease in children. Due to the lack of an animal model, its pathogenetic mechanism is poorly understood. To study the role of AADC in brain development, a zebrafish model of AADC deficiency was generated. We identified an aadc gene homolog, dopa decarboxylase (ddc), in the zebrafish genome. Whole-mount in situ hybridization analysis showed that the ddc gene is expressed in the epiphysis, locus caeruleus, diencephalic catecholaminergic clusters, and raphe nuclei of 36-h post-fertilization (hpf) zebrafish embryos. Inhibition of Ddc by AADC inhibitor NSD-1015 or anti-sense morpholino oligonucleotides (MO) reduced brain volume and body length. We observed increased brain cell apoptosis and loss of dipencephalic catecholaminergic cluster neurons in ddc morphants (ddc MO-injected embryos). Seizure-like activity was also detected in ddc morphants in a dose-dependent manner. ddc morphants had less sensitive touch response and impaired swimming activity that could be rescued by injection of ddc plasmids. In addition, eye movement was also significantly impaired in ddc morphants. Collectively, loss of Ddc appears to result in similar phenotypes as that of ADCC deficiency, thus zebrafish could be a good model for investigating pathogenetic mechanisms of AADC deficiency in children.
Institute of Zoology, National Taiwan University, Taipei, Taiwan, R.O.C.
De-Fen
DF
Shih
Chung-Der
CD
Hsiao
Ming-Yuan
MY
Min
Wen-Sung
WS
Lai
Chianne-Wen
CW
Yang
Wang-Tso
WT
Lee
Shyh-Jye
SJ
Lee
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics / Q000502:physiology*; D001921:Brain / Q000196:embryology*; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000235:genetics*; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
D001142:Aromatic-L-Amino-Acid Decarboxylases