Wdfy3调节糖吞噬、线粒体自噬和突触可塑性。

Eleonora Napoli, Alexios A Panoutsopoulos, Patricia Kysar, Nathaniel Satriya, Kira Sterling, Bradley Shibata, Denise Imai, David N Ruskin, Konstantinos S Zarbalis, Cecilia Giulivi
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引用次数: 6

摘要

自噬对细胞功能至关重要,因为它能够在饥饿期间实现细胞内成分的再循环,此外,通过消除如果不适当清除可能导致细胞损伤的废细胞器和蛋白质,它还具有质量控制机制。最近,我们报道了Wdfy3在线粒体自噬中的作用,线粒体自噬是一种临床相关的巨噬支架蛋白,与智力残疾、神经发育迟缓和自闭症谱系障碍有关。在本研究中,我们证实了我们之前的报道,即小鼠Wdfy3单倍性不足导致线粒体自噬减少,线粒体积聚,形态学改变,但在此观察基础上,我们还注意到突触末端线粒体定位减少,突触密度降低,这可能导致突触可塑性改变。这些变化伴随着糖原颗粒消除的缺陷和糖原合成的增加而不是糖原分解和糖吞噬。这种不平衡导致小脑发育不全时脑糖原沉积的年龄依赖性较高。我们的研究结果支持并进一步扩展了Wdfy3在调节脑生物能量学和突触可塑性中的作用,通过将糖原作为大自噬降解的靶标。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Wdfy3 regulates glycophagy, mitophagy, and synaptic plasticity.

Wdfy3 regulates glycophagy, mitophagy, and synaptic plasticity.

Autophagy is essential to cell function, as it enables the recycling of intracellular constituents during starvation and in addition functions as a quality control mechanism by eliminating spent organelles and proteins that could cause cellular damage if not properly removed. Recently, we reported on Wdfy3's role in mitophagy, a clinically relevant macroautophagic scaffold protein that is linked to intellectual disability, neurodevelopmental delay, and autism spectrum disorder. In this study, we confirm our previous report that Wdfy3 haploinsufficiency in mice results in decreased mitophagy with accumulation of mitochondria with altered morphology, but expanding on that observation, we also note decreased mitochondrial localization at synaptic terminals and decreased synaptic density, which may contribute to altered synaptic plasticity. These changes are accompanied by defective elimination of glycogen particles and a shift to increased glycogen synthesis over glycogenolysis and glycophagy. This imbalance leads to an age-dependent higher incidence of brain glycogen deposits with cerebellar hypoplasia. Our results support and further extend Wdfy3's role in modulating both brain bioenergetics and synaptic plasticity by including glycogen as a target of macroautophagic degradation.

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