Homozygotic mutations in the GBA gene cause Gaucher’s disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson’s disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher’s disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice. Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins. This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication.

中文翻译：

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小胶质细胞β-葡萄糖脑苷脂酶的抑制阻碍了小胶质细胞介导的神经元抗氧化和保护反应

GBA基因的纯合突变导致戈谢病；此外，患者和杂合子携带者患帕金森病的风险增加了 20 到 30 倍。在纯合子中，这些突变会损害由 GBA 编码的酶 β-葡萄糖脑苷脂酶的活性，并在巨噬细胞中产生溶酶体紊乱，从而将形态学改变为充血表型，这被认为是戈谢病的标志。尽管巨噬细胞在这种疾病中起关键作用，但大脑中的大部分影响都归因于神经元中的 β-葡萄糖脑苷脂酶缺陷，而这些突变的小胶质细胞表型从未被报道过。我们应用了生物发光成像技术，免疫组织化学和基因表达分析，以研究小胶质细胞 β-葡萄糖脑苷脂酶抑制在报告小鼠大脑、原代神经元/小胶质细胞共培养物和细胞系中的后果。使用来自报告小鼠的原代细胞首次允许在共培养物中区分神经元和由 β-葡萄糖脑苷脂酶抑制引起的小胶质细胞反应；结果最终通过小鼠大脑中小胶质细胞的药理学耗竭得到证实。我们的数据表明存在一种由功能性肌动蛋白结构支持的直接小胶质细胞与神经元接触介导的新型神经保护机制。这种细胞接触刺激神经元中的核因子红细胞 2 相关因子 2 活性，这是参与药物解毒、氧化还原平衡、新陈代谢、自噬、溶酶体生物发生、线粒体功能障碍和神经炎症。小胶质细胞在体内这种神经元反应中所起的核心作用已通过报告小鼠大脑中谱系的耗竭得到证实。小胶质细胞β-葡萄糖脑苷脂酶的药理抑制被证明可诱导形态变化，开启抗炎/修复途径，并阻碍小胶质细胞激活核因子红细胞2相关因子2反应的能力，从而增加神经元对神经毒素。这种机制为在 GBA 突变携带者中观察到的神经变性风险增加提供了可能的解释，并提出了旨在恢复与 β-葡萄糖脑苷脂酶抑制相关的小胶质细胞表型的新治疗策略，