Autophagy is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodelling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS). Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified superoxide dismutase 1, an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased mTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point towards an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and mTOR-dependent autophagy.

中文翻译：

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KANSL1缺乏症通过氧化应激诱导的自噬导致神经元功能障碍。

自噬是蛋白质和细胞成分的程序化降解和再循环的微调过程，这对神经元功能和突触完整性至关重要。越来越多的证据表明，染色质在微调自噬途径中的重塑。但是，这种表观遗传调控在神经元中了解甚少。在这里，我们调查KANSL1，非特异性致死复合物的成员在自噬中的作用，该物质使赖氨酸16（H4K16ac）上的组蛋白H4乙酰化，以促进转录激活。KANSL1的功能丧失与神经发育障碍Koolen-de Vries综合征（KdVS）密切相关。从KdVS患者和基因组编辑的系中，从缺乏KANSL1的人诱导多能干细胞开始，我们发现抗氧化物酶超氧化物歧化酶1显着降低，导致氧化应激和自噬小体积累的增加。在KANSL1缺失的神经元中，自噬体在兴奋性突触处的积累导致突触密度降低，AMPA受体介导的传递降低以及神经元网络活动受损。此外，我们发现增加的氧化应激介导的自噬体积累导致mTOR活化增加和溶酶体功能降低，从而进一步阻止了自噬体的清除。最后，通过药理学降低氧化应激，我们可以挽救KANSL1缺陷神经元的异常自噬体形成以及突触和神经元网络活动。因此，我们的发现指出了氧化应激诱导的自噬与突触功能之间的重要关系，