Department of Pharmacy, Children's Hospital of Soochow University, Suzhou 215000, China.
Department of Pharmacy, Children's Hospital of Soochow University, Suzhou 215000, China; Kangda College of Nanjing Medical University, Nanjing 210000, China.
Neuroscience. 2021 Jun 15;465:85-94. doi: 10.1016/j.neuroscience.2021.04.010. Epub 2021 Apr 22.
Autism spectrum disorder (ASD) is a widespread, complex and serious neurodevelopmental disorder. Complex genetic and environmental factors are thought to contribute to the development of ASD. Genome-wide association analysis has identified multiple autism-related genes. Mutation of the phosphatase and tensin homolog (Pten) is closely related to autism and accounts for 5-17% of cases of autism. However, the detailed mechanism is still unclear. Recently, mitochondrial dysfunction was tightly associated with ASD pathogenesis, such as developmental degeneration, learning and various behavioral disorders. The mitochondrial DNA (mtDNA) copy number in children with autism is also significantly increased. The correlation between Pten and mitochondrial dysfunction in autism is still unknown. In this study, we examined how Pten regulates mitochondrial biogenesis through the AKT/GSK-3β/PGC-1α signaling pathways. We found that PTEN could dephosphorylate AKT to inhibit its activity, leading to decreased GSK3β phosphorylation. This decrease in GSK3β phosphorylation, which could activate itself, increased PGC-1α phosphorylation to promote its degradation and then regulated mitochondrial biogenesis by NRF-1 and TFAM downstream of PGC-1α. In the Valproic acid (VPA) induced autism mouse model, the PTEN protein level was significantly decreased while PGC-1α and COX IV levels were increased in the hippocampus and cortex. Our data suggest that there is a correlation between PTEN and mitochondrial dysfunction and this correlation may be a potential mechanism of ASD.
自闭症谱系障碍（ASD）是一种广泛存在的、复杂的、严重的神经发育障碍。复杂的遗传和环境因素被认为是 ASD 发展的原因。全基因组关联分析已经确定了多个与自闭症相关的基因。磷酸酶和张力蛋白同系物（Pten）的突变与自闭症密切相关，占自闭症病例的 5-17%。然而，其详细的机制仍不清楚。最近，线粒体功能障碍与 ASD 的发病机制密切相关，如发育退化、学习和各种行为障碍。自闭症儿童的线粒体 DNA（mtDNA）拷贝数也显著增加。Pten 与自闭症中线粒体功能障碍之间的相关性尚不清楚。在这项研究中，我们研究了 Pten 通过 AKT/GSK-3β/PGC-1α 信号通路如何调节线粒体生物发生。我们发现 PTEN 可以去磷酸化 AKT 以抑制其活性，导致 GSK3β 磷酸化减少。这种 GSK3β 磷酸化的减少，自身活性增加，增加了 PGC-1α 的磷酸化，促进其降解，然后通过 PGC-1α 下游的 NRF-1 和 TFAM 调节线粒体生物发生。在丙戊酸（VPA）诱导的自闭症小鼠模型中，海马体和皮质中的 PTEN 蛋白水平显著降低，而 PGC-1α 和 COX IV 水平升高。我们的数据表明，PTEN 与线粒体功能障碍之间存在相关性，这种相关性可能是 ASD 的潜在机制之一。
