Miyazaki Shuya, Shimizu Nobuyuki, Miyahara Hiroaki, Teranishi Hitoshi, Umeda Ryohei, Yano Shinji, Shimada Tatsuo, Shiraishi Hiroshi, Komiya Kosaku, Katoh Akira, Yoshimura Akihiko, Hanada Reiko, Hanada Toshikatsu
Department of Cell Biology, Oita University Faculty of Medicine, Yufu, Oita, Japan; Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, Yufu, Oita, Japan.
Department of Cell Biology, Oita University Faculty of Medicine, Yufu, Oita, Japan.
Biochem Biophys Res Commun. 2024 Jun 18;712-713:149932. doi: 10.1016/j.bbrc.2024.149932. Epub 2024 Apr 12.
The DHCR7 enzyme converts 7-DHC into cholesterol. Mutations in DHCR7 can block cholesterol production, leading to abnormal accumulation of 7-DHC and causing Smith-Lemli-Opitz syndrome (SLOS). SLOS is an autosomal recessive disorder characterized by multiple malformations, including microcephaly, intellectual disability, behavior reminiscent of autism, sleep disturbances, and attention-deficit/hyperactivity disorder (ADHD)-like hyperactivity. Although 7-DHC affects neuronal differentiation in ex vivo experiments, the precise mechanism of SLOS remains unclear. We generated Dhcr7 deficient (dhcr7) zebrafish that exhibited key features of SLOS, including microcephaly, decreased neural stem cell pools, and behavioral phenotypes similar to those of ADHD-like hyperactivity. These zebrafish demonstrated compromised myelination, synaptic anomalies, and neurotransmitter imbalances. The axons of the dhcr7 zebrafish showed increased lysosomes and attenuated autophagy, suggesting that autophagy-related neuronal homeostasis is disrupted.
DHCR7 酶将 7-DHC 转化为胆固醇。DHCR7 中的突变会阻断胆固醇的产生，导致 7-DHC 异常蓄积，并引发史密斯-勒米-奥皮茨综合征（SLOS）。SLOS 是一种常染色体隐性疾病，其特征为多种畸形，包括小头畸形、智力残疾、类似自闭症的行为、睡眠障碍以及类似注意力缺陷多动障碍（ADHD）的多动。尽管在体外实验中 7-DHC 会影响神经元分化，但 SLOS 的精确机制仍不清楚。我们培育出了表现出 SLOS 关键特征的 Dhcr7 缺陷型（dhcr7）斑马鱼，这些特征包括小头畸形、神经干细胞池减少以及类似于 ADHD 样多动的行为表型。这些斑马鱼表现出髓鞘形成受损、突触异常和神经递质失衡。dhcr7 斑马鱼的轴突显示溶酶体增加且自噬减弱，这表明与自噬相关的神经元内环境稳定受到破坏。
