自噬
UBE3A公司
泛素连接酶
安普克
化学
细胞生物学
小脑
内分泌学
激活剂(遗传学)
贝肯1
内科学
泛素
生物
磷酸化
受体
蛋白激酶A
生物化学
基因
医学
细胞凋亡
作者
Xiaoning Hao,Jiandong Sun,Li Zhong,Michel Baudry,Xiaoning Bi
标识
DOI:10.1016/j.expneurol.2023.114358
摘要
Angelman Syndrome (AS) is a neurodevelopmental disorder caused by deficiency of the maternally expressed UBE3A gene. The UBE3A proteins functions both as an E3 ligase in the ubiquitin-proteasome system (UPS), and as a transcriptional co-activator for steroid hormone receptors. Here we investigated the effects of UBE3A deficiency on autophagy in the cerebellum of AS mice and in COS1 cells. Numbers and size of LC3- and LAMP2-immunopositive puncta were increased in cerebellar Purkinje cells of AS mice, as compared to wildtype mice. Western blot analysis showed an increase in the conversion of LC3I to LC3II in AS mice, as expected from increased autophagy. Levels of active AMPK and of one of its substrates, ULK1, a factor involved in autophagy initiation, were also increased. Colocalization of LC3 with LAMP2 was increased and p62 levels were decreased, indicating an increase in autophagy flux. UBE3A deficiency was also associated with reduced levels of phosphorylated p53 in the cytosol and increased levels in nuclei, which favors autophagy induction. UBE3A siRNA knockdown in COS-1 cells resulted in increased size and intensity of LC3-immunopositive puncta and increased the LC3 II/I ratio, as compared to control siRNA-treated cells, confirming the results found in the cerebellum of AS mice. These results indicate that UBE3A deficiency enhances autophagic activity through activation of the AMPK-ULK1 pathway and alterations in p53.
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