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首页> 外文期刊>Human Molecular Genetics >Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1
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Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1

机译：神经元Tsc1 / 2复合物通过依赖AMPK的ULK1调控来控制自噬

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Tuberous sclerosis complex (TSC) is a disorder arising from mutation in the TSC1 or TSC2 gene, characterized by the development of hamartomas in various organs and neurological manifestations including epilepsy, intellectual disability and autism. TSC1/2 protein complex negatively regulates the mammalian target of rapamycin complex 1 (mTORC1) amaster regulator of protein synthesis, cell growth and autophagy. Autophagy is a cellular quality-control process that sequesters cytosolic material in double membrane vesicles called autophagosomes and degrades it in autolysosomes. Previous studies in dividing cells have shown that mTORC1 blocks autophagy through inhibition of Unc-51-like-kinase1/2 (ULK1/2). Despite the fact that autophagy plays critical roles in neuronal homeostasis, little is known on the regulation of autophagy in neurons. Here we show that unlike in non-neuronal cells, Tsc2-deficient neurons have increased autolysosome accumulation and autophagic flux despite mTORC1-dependent inhibition of ULK1. Our data demonstrate that loss of Tsc2 results in autophagic activity via AMPK-dependent activation of ULK1. Thus, in Tsc2-knockdown neurons AMPK activation is the dominant regulator of autophagy. Notably, increased AMPK activity and autophagy activation are also found in the brains of Tsc1-conditional mouse models and in cortical tubers resected from TSC patients. Together, our findings indicate that neuronal Tsc1/2 complex activity is required for the coordinated regulation of autophagy by AMPK. By uncovering the autophagy dysfunction associated with Tsc2 loss in neurons, our work sheds light on a previously uncharacterized cellular mechanism that contributes to altered neuronal homeostasis in TSC disease.
机译：结节性硬化症（TSC）是由TSC1或TSC2基因突变引起的疾病，其特征是各个器官中错构瘤的发展以及包括癫痫，智力障碍和自闭症在内的神经系统表现。 TSC1 / 2蛋白复合物负调节雷帕霉素复合物1（mTORC1）的哺乳动物靶标，而蛋白合成，细胞生长和自噬是主要调节剂。自噬是一种细胞质量控制过程，其将被称为自噬小体的双膜囊泡中的胞质物质隔离并使其降解为自溶酶体。先前对分裂细胞的研究表明，mTORC1通过抑制Unc-51-like-kinase1 / 2（ULK1 / 2）来阻止自噬。尽管自噬在神经元稳态中起着关键作用，但对神经元自噬的调控知之甚少。在这里我们表明，与非神经元细胞不同，尽管存在mTORC1依赖性的ULK1抑制作用，Tsc2缺陷型神经元却增加了溶酶体积累和自噬通量。我们的数据表明，Tsc2的丢失通过AMPK依赖性的ULK1激活导致自噬活性。因此，在Tsc2击倒神经元中，AMPK激活是自噬的主要调节因子。值得注意的是，在Tsc1条件小鼠模型的大脑和从TSC患者切除的皮质块茎中也发现了AMPK活性增加和自噬激活。在一起，我们的研究结果表明神经元Tsc1 / 2复杂的活动是AMPK的自噬协调调控所必需的。通过揭示与神经元中Tsc2丢失相关的自噬功能障碍，我们的工作揭示了以前未知的细胞机制，该机制导致TSC疾病的神经元稳态改变。

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