A multifaceted evaluation of microgliosis and differential cellular dysregulation of mammalian target of rapamycin signaling in neuronopathic Gaucher disease.
A multifaceted evaluation of microgliosis and differential cellular dysregulation of mammalian target of rapamycin signaling in neuronopathic Gaucher disease.
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DOI：
10.3389/fnmol.2022.944883
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发表时间：
2022
影响因子：
4.8
通讯作者：
Pan, Dao
中科院分区：
文献类型：
--
作者：
Zhang, Zhenting;Wang, Xiaohong;Lin, Yi;Pan, Dao
关键词：
神经性戈谢病（nGD）是一种由GBA1基因突变引起的遗传性神经退行性疾病，与过早死亡有关。神经炎症在以小胶质细胞增生、反应性星形细胞增生和神经元丢失为特征的疾病发病机制中起着至关重要的作用，尽管导致神经炎症的分子机制尚不清楚。在本报告中，我们开发了一种方便的工具来独立量化小胶质细胞的增殖和激活，并在成人遗传nGD模型中发现了小胶质细胞的异常增殖（~ 2倍）。确定了与小胶质细胞表型相关的炎症介质的ngd相关模式，显示出有利于促炎趋化因子和细胞因子的独特特征。此外，在nGD脑的三种主要细胞类型中，观察到mTORC1信号的高度极化（向上或向下）失调，并伴有不同的溶酶体功能障碍（数量和体积）。具体来说，在所有疾病相关的小胶质细胞（Iba1high）中检测到过度活跃的mTORC1信号，同时溶酶体功能增加。相反，具有高mTORC1活性的神经元（包括浦肯病样细胞）的减少与nGD小鼠溶酶体功能的不一致变化有关。在患病小鼠和正常小鼠的星形胶质细胞中都发现了检测不到的mTORC1活性水平和低Lamp1点，这表明mTORC1途径和溶酶体功能在疾病相关星形胶质细胞中有轻微的参与。这些发现突出了不同类型的大脑细胞所涉及的分子机制的差异和复杂性。建立的可量化参数和确定的神经炎症介质的ngd相关模式，将有助于评估小胶质瘤的疗效，并进一步发现治疗神经性戈谢病的新治疗靶点。
Neuronopathic Gaucher disease (nGD) is an inherited neurodegenerative disease caused by mutations in GBA1 gene and is associated with premature death. Neuroinflammation plays a critical role in disease pathogenesis which is characterized by microgliosis, reactive astrocytosis, and neuron loss, although molecular mechanisms leading to neuroinflammation are not well-understood. In this report, we developed a convenient tool to quantify microglia proliferation and activation independently and uncovered abnormal proliferation of microglia (∼2-fold) in an adult genetic nGD model. The nGD-associated pattern of inflammatory mediators pertinent to microglia phenotypes was determined, showing a unique signature favoring pro-inflammatory chemokines and cytokines. Moreover, highly polarized (up or down) dysregulations of mTORC1 signaling with varying lysosome dysfunctions (numbers and volume) were observed among three major cell types of nGD brain. Specifically, hyperactive mTORC1 signaling was detected in all disease-associated microglia (Iba1high) with concurrent increase in lysosome function. Conversely, the reduction of neurons presenting high mTORC1 activity was implicated (including Purkinje-like cells) which was accompanied by inconsistent changes of lysosome function in nGD mice. Undetectable levels of mTORC1 activity and low Lamp1 puncta were noticed in astrocytes of both diseased and normal mice, suggesting a minor involvement of mTORC1 pathway and lysosome function in disease-associated astrocytes. These findings highlight the differences and complexity of molecular mechanisms that are involved within various cell types of the brain. The quantifiable parameters established and nGD-associated pattern of neuroinflammatory mediators identified would facilitate the efficacy evaluation on microgliosis and further discovery of novel therapeutic target(s) in treating neuronopathic Gaucher disease.
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