Department of Neurobiology, Stanford University, Fairchild D200, 299 W. Campus Drive, Stanford, CA 94305, USA.
Department of Psychology and Neuroscience, Life Sciences Centre, Dalhousie University, Halifax, NS B3H 4R2, Canada.
Neuron. 2019 Feb 20;101(4):721-737.e4. doi: 10.1016/j.neuron.2019.01.015. Epub 2019 Feb 5.
Neurons can maintain stable synaptic connections across adult life. However, the signals that regulate expression of synaptic proteins in the mature brain are incompletely understood. Here, we describe a transcriptional feedback loop between the biosynthesis and repertoire of specific phospholipids and the synaptic vesicle pool in adult Drosophila photoreceptors. Mutations that disrupt biosynthesis of a subset of phospholipids cause degeneration of the axon terminal and loss of synaptic vesicles. Although degeneration of the axon terminal is dependent on neural activity, activation of sterol regulatory element binding protein (SREBP) is both necessary and sufficient to cause synaptic vesicle loss. Our studies demonstrate that SREBP regulates synaptic vesicle levels by interacting with tetraspanins, critical organizers of membranous organelles. SREBP is an evolutionarily conserved regulator of lipid biosynthesis in non-neuronal cells; our studies reveal a surprising role for this feedback loop in maintaining synaptic vesicle pools in the adult brain.
神经元可以在成年期维持稳定的突触连接。然而，调节成熟大脑中突触蛋白表达的信号尚不完全清楚。在这里，我们描述了成年果蝇光感受器中特定磷脂的生物合成和库与突触小泡池之间的转录反馈回路。破坏一组特定磷脂生物合成的突变会导致轴突末梢退化和突触小泡丢失。尽管轴突末梢的退化依赖于神经活动，但固醇调节元件结合蛋白 (SREBP) 的激活既是必需的，也是导致突触小泡丢失的充分条件。我们的研究表明，SREBP 通过与四跨膜蛋白相互作用来调节突触小泡水平，四跨膜蛋白是膜细胞器的关键组织者。SREBP 是非神经元细胞中脂质生物合成的进化保守调节剂；我们的研究揭示了这种反馈回路在维持成年大脑中突触小泡池中的惊人作用。
