芳香族 L-胺基酸脫羧酵素在腦發育與運動功能佔有重要角色

Abstract

芳香族 L-氨基酸脫羧酶（AADC）缺乏症是一種罕見的兒童神經代謝性疾病。由於缺乏動物模型的參考，其致病機理目前所知甚少。本文主旨為產生AADC缺乏症的斑馬魚模型，以供未來研究AADC相關病理機制之用。原位雜交分析中顯示AADC基因在受精36小時後的斑馬魚胚胎中腦部的骨骺(epiphysis), 藍斑核(locus coeruleus), 間腦兒茶酚胺聚集(dipencephalic catecholaminergic clusters，DC), and 中縫核(raphe nuclei)有特別高的表現。使用AADC抑製劑NSD-1015或反股嗎

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. Whole-mount in situ hybridization analysis showed that the aadc gene was specifically expressed in the epiphysis, locus coeruleus, dipencephalic catecholaminergic (DC) clusters, and raphe nuclei of 36-h post-fertilization (hpf) zebrafish embryos. Inhibition of AADC by the inhibitor NSD-1015 or anti-sense morpholino (MO) led to a reduction brain volume and body length. There was an increased apoptosis occurrence in the brain and a loss of DC cluster neurons in AADC morphants (aadc MO-injected embryos). Seizure-like activity was also detected in AADC morphants in a dose-dependent manner. The AADC morphants were less sensitive in touch response and had a reduced swimming activity, and these phenotypes were rescued by injection of aadc plasmids. In conclusion, inhibition of AADC may reduce brain size, increase apoptosis, and reduce motor function in zebrafish. Zebrafish can be a useful model for investigating the pathogenetic mechanisms of AADC deficiency in children.