Institute of Molecular Genetics of RAS, Kurchatov Sq. 2, 123182, Moscow, Russia.
Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkin 3, Moscow 119991, Russia.
Int J Mol Sci. 2019 May 4;20(9):2200. doi: 10.3390/ijms20092200.
GSK3 (glycogen synthase kinase 3) is a conserved protein kinase governing numerous regulatory pathways. In , GSK3 is encoded by (), which forms 17 annotated transcripts corresponding to 10 protein isoforms. Our goal was to demonstrate how differential transcription affects lifespan, which GSK3 isoforms are important for the nervous system, and which changes in the nervous system accompany accelerated aging. Overexpression of three transcripts affected the lifespan in a stage- and tissue-specific way: and affected the lifespan only when overexpressed in muscles and in embryos, respectively; the essential transcript affected lifespan when overexpressed in all tissues tested. In the nervous system, only overexpression affected lifespan, causing accelerated aging in a neuron-specific way, with the strongest effects in dopaminergic neurons and the weakest effects in GABAergic neurons. Pan-neuronal - overexpression violated the properties of the nervous system, including the integrity of neuron bodies; the number, distribution, and structure of mitochondria; cytoskeletal characteristics; and synaptic activity. Such changes observed in young individuals indicated premature aging of their nervous system, which paralleled a decline in survival. Our findings demonstrated the key role of GSK3 in ensuring the link between the pathology of neurons and lifespan.
GSK3（糖原合成酶激酶 3）是一种保守的蛋白激酶，调控着众多的调控途径。在，GSK3 由编码，它形成 17 个注释转录本，对应 10 种蛋白同工型。我们的目标是展示差异转录如何影响寿命，哪些 GSK3 同工型对神经系统很重要，以及哪些神经系统的变化伴随着衰老的加速。三种的过表达以阶段和组织特异性的方式影响寿命：和分别仅在肌肉和胚胎中过表达时才影响寿命；必需的转录本在所有测试的组织中过表达时影响寿命。在神经系统中，只有过表达影响寿命，以神经元特异性的方式导致衰老加速，在多巴胺能神经元中的影响最强，在 GABA 能神经元中的影响最弱。泛神经元的过表达破坏了神经系统的特性，包括神经元体的完整性；线粒体的数量、分布和结构；细胞骨架特征；和突触活性。在年轻人中观察到的这些变化表明他们的神经系统提前衰老，这与生存能力的下降相平行。我们的研究结果表明，GSK3 在确保神经元病理与寿命之间的联系方面起着关键作用。
