Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes.
Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes.
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Synaptojanin1 缺陷会上调星形胶质细胞中基础自噬体的形成。
DOI：
10.1016/j.jbc.2021.100873
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Dreyfus CF
中科院分区：
文献类型：
--
作者：
Pan PY;Zhu J;Rizvi A;Zhu X;Tanaka H;Dreyfus CF
巨自噬功能失调与多种神经系统疾病有关，如帕金森氏症。虽然在异种细胞和神经元中对自噬途径进行了大量的研究，但对哺乳动物大脑中最丰富的细胞类型星形胶质细胞自噬的调控却知之甚少。Synj1基因编码Synaptojanin1(Synj1)的错义突变被认为与帕金森氏症伴癫痫有关。Synj1是一种神经元丰富的脂质磷酸酶。我们之前的研究表明，Synj1单倍体不足(Synj1+/−)小鼠在多个脑区表现出年龄相关性的自噬障碍。在这里，我们使用培养的来自Synj1缺陷小鼠的星形胶质细胞来研究它在星形胶质细胞自噬中的作用。我们报道Synj1在星形胶质细胞中低水平表达，并抑制基础自噬小体的形成。我们利用细胞成像技术证明了Synj1缺陷的星形胶质细胞表现出过度活跃的自噬小体形成，表现为GFP-微管相关蛋白1A/1B-轻链3结构的大小和数量的增加。有趣的是，Synj1缺乏也与应激诱导的自噬清除障碍有关。我们首次发现，与帕金森病相关的R839C突变影响了星形胶质细胞的自噬。该突变对Synj1磷酸酶功能的影响导致模拟Synj1缺失的基础自噬小体形成增加。我们发现，在Synj1缺陷的星形胶质细胞中，星形胶质细胞特异性葡萄糖转运体GLUT-1的膜表达减少。一如既往，AMP激活的蛋白激酶活性升高，这表明Synj1缺陷的星形胶质细胞的葡萄糖感觉发生了变化。在Synj1缺陷的星形胶质细胞中表达外源性GLUT-1可以逆转自噬损伤，支持Synj1通过破坏葡萄糖感知通路来调节星形胶质细胞的自噬。因此，我们的工作提出了Synj1相关帕金森综合征的一种新机制，涉及星形胶质细胞功能障碍。
Macroautophagy dysregulation is implicated in multiple neurological disorders, such as Parkinson's disease. While autophagy pathways are heavily researched in heterologous cells and neurons, regulation of autophagy in the astrocyte, the most abundant cell type in the mammalian brain, is less well understood. Missense mutations in the Synj1 gene encoding Synaptojanin1 (Synj1), a neuron-enriched lipid phosphatase, have been linked to Parkinsonism with seizures. Our previous study showed that the Synj1 haploinsufficient (Synj1+/−) mouse exhibits age-dependent autophagy impairment in multiple brain regions. Here, we used cultured astrocytes from Synj1-deficient mice to investigate its role in astrocyte autophagy. We report that Synj1 is expressed in low levels in astrocytes and represses basal autophagosome formation. We demonstrate using cellular imaging that Synj1-deficient astrocytes exhibit hyperactive autophagosome formation, represented by an increase in the size and number of GFP-microtubule-associated protein 1A/1B-light chain 3 structures. Interestingly, Synj1 deficiency is also associated with an impairment in stress-induced autophagy clearance. We show, for the first time, that the Parkinsonism-associated R839C mutation impacts autophagy in astrocytes. The impact of this mutation on the phosphatase function of Synj1 resulted in elevated basal autophagosome formation that mimics Synj1 deletion. We found that the membrane expression of the astrocyte-specific glucose transporter GluT-1 was reduced in Synj1-deficient astrocytes. Consistently, AMP-activated protein kinase activity was elevated, suggesting altered glucose sensing in Synj1-deficient astrocytes. Expressing exogenous GluT-1 in Synj1-deficient astrocytes reversed the autophagy impairment, supporting a role for Synj1 in regulating astrocyte autophagy via disrupting glucose-sensing pathways. Thus, our work suggests a novel mechanism for Synj1-related Parkinsonism involving astrocyte dysfunction.
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