Neuroinflammation in Gaucher disease, neuronal ceroid lipofuscinosis, and commonalities with Parkinson's disease.
Neuroinflammation in Gaucher disease, neuronal ceroid lipofuscinosis, and commonalities with Parkinson's disease.
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DOI：
10.1016/j.brainres.2022.147798
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发表时间：
2022-04-01
期刊：
影响因子：
2.9
通讯作者：
中科院分区：
文献类型：
--
作者：
溶酶体储存疾病(LSD)是一种罕见的遗传性疾病，由细胞清除中断引起，导致未降解的溶酶体底物病理性储存。最近的临床和遗传学研究发现，多发性LSD与常见的神经退行性疾病，如帕金森氏病(PD)之间存在联系。在这里，我们回顾了最近的文献，描述了胶质细胞和神经炎症在PD和LSD中的作用，包括Gaucher病(GD)和神经性蜡样脂褐素沉着症(NCL)，并强调了导致神经元丢失的汇聚性炎症途径。最近的数据表明，溶酶体功能障碍和储存物质的积累可以通过与细胞表面或细胞质模式识别受体相互作用来启动神经胶质细胞的激活，这些受体检测细胞碎片的病理性聚集。激活的胶质细胞可以通过在疾病过程的早期消除有毒的蛋白质或脂肪聚集体来保护神经元。然而，在慢性年龄相关性神经退行性变中，长达数十年的胶质细胞激活可能会导致突触的不适当消除，导致神经元丢失。这些研究为溶酶体功能障碍和神经胶质细胞激活之间的关系提供了机械性的见解，并为PD和LSD的治疗提供了新的治疗途径，重点是减少神经炎症和减轻细胞丢失。
Lysosomal storage diseases (LSDs) are rare genetic disorders caused by a disruption in cellular clearance, resulting in pathological storage of undegraded lysosomal substrates. Recent clinical and genetic studies have uncovered links between multiple LSDs and common neurodegenerative diseases such as Parkinson’s disease (PD). Here, we review recent literature describing the role of glia cells and neuroinflammation in PD and LSDs, including Gaucher disease (GD) and neuronal ceroid lipofuscinosis (NCL), and highlight converging inflammation pathways that lead to neuron loss. Recent data indicates that lysosomal dysfunction and accumulation of storage materials can initiate the activation of glial cells, through interaction with cell surface or cytosolic pattern recognition receptors that detect pathogenic aggregates of cellular debris. Activated glia cells could act to protect neurons through the elimination of toxic protein or lipid aggregates early in the disease process. However prolonged glial activation that occurs over several decades in chronic-age related neurodegeneration could induce the inappropriate elimination of synapses, leading to neuron loss. These studies provide mechanistic insight into the relationship between lysosomal dysfunction and glial activation, and offer novel therapeutic pathways for the treatment of PD and LSDs focused on reducing neuroinflammation and mitigating cell loss.
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