BACKGROUND Lysosomal storage diseases (LSD) are a large family of inherited disorders characterized by abnormal endolysosomal accumulation of cellular material due to catabolic enzyme and transporter deficiencies. Depending on the affected metabolic pathway, LSD manifest with somatic or central nervous system (CNS) signs and symptoms. Neuroinflammation is a hallmark feature of LSD with CNS involvement such as mucolipidosis type IV, but not of others like Fabry disease. METHODS We investigated the properties of microglia from LSD with and without major CNS involvement in 2-month-old mucolipidosis type IV (Mcoln1-/-) and Fabry disease (Glay/-) mice, respectively, by using a combination of flow cytometric, RNA sequencing, biochemical, in vitro and immunofluorescence analyses. RESULTS We characterized microglia activation and transcriptome from mucolipidosis type IV and Fabry disease mice to determine if impaired lysosomal function is sufficient to prime these brain-resident immune cells. Consistent with the neurological pathology observed in mucolipidosis type IV, Mcoln1-/- microglia demonstrated an activation profile with a mixed neuroprotective/neurotoxic expression pattern similar to the one we previously observed in Niemann-Pick disease, type C1, another LSD with significant CNS involvement. In contrast, the Fabry disease microglia transcriptome revealed minimal alterations, consistent with the relative lack of CNS symptoms in this disease. The changes observed in Mcoln1-/- microglia showed significant overlap with alterations previously reported for other common neuroinflammatory disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Indeed, our comparison of microglia transcriptomes from Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick disease, type C1 and mucolipidosis type IV mouse models showed an enrichment in "disease-associated microglia" pattern among these diseases. CONCLUSIONS The similarities in microglial transcriptomes and features of neuroinflammation and microglial activation in rare monogenic disorders where the primary metabolic disturbance is known may provide novel insights into the immunopathogenesis of other more common neuroinflammatory disorders. TRIAL REGISTRATION ClinicalTrials.gov, NCT01067742, registered on February 12, 2010.

中文翻译：

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IV型小胶质细胞粘液病的独特分子特征。

背景技术溶酶体贮积病（LSD）是一大类遗传性疾病，其特征在于由于分解代谢酶和转运蛋白缺陷导致细胞物质的溶酶体异常积累。根据受影响的代谢途径，LSD表现出躯体或中枢神经系统（CNS）的体征和症状。神经发炎是LSD的标志性特征，它涉及CNS，例如IV型粘膜脂溢性疾病，但不包括法布里氏病这样的其他疾病。方法我们采用流式细胞仪技术，分别研究了2个月大的IV型Mconlipidosis IV型（Mcoln1-/-）和Fabry病（Glay /-）小鼠在有和没有主要CNS的情况下来自LSD的小胶质细胞的特性， RNA测序，生化，体外和免疫荧光分析。结果我们表征了IV型粘脂病和法布里病小鼠的小胶质细胞激活和转录组，以确定溶酶体功能受损是否足以引发这些脑部驻留的免疫细胞。与IV型黏膜脂溢病中观察到的神经病理学一致，Mcoln1-/-小胶质细胞显示出一种激活模式，具有混合的神经保护/神经毒性表达模式，类似于我们先前在Niemann-Pick病中观察到的C1型，另一种与中枢神经系统受累的LSD 。相反，法布里（Fabry）病小胶质细胞转录组显示出最小的变化，与这种疾病中CNS症状的相对缺乏相一致。在Mcoln1-/-小胶质细胞中观察到的变化与先前报道的其他常见神经炎性疾病（包括阿兹海默氏症，帕金森氏症和亨廷顿氏病）的变化显着重叠。实际上，我们对阿尔茨海默氏病，肌萎缩性侧索硬化症，Niemann-Pick病，C1型和IV型黏液脂病小鼠模型的小胶质细胞转录组的比较显示，这些疾病中“疾病相关的小胶质细胞”模式有所丰富。结论在已知原发性代谢紊乱的罕见单基因疾病中，小胶质细胞转录组的相似性以及神经炎症和小胶质细胞激活的特征可能为其他更常见的神经炎性疾病的免疫发病机制提供新的见解。试验注册ClinicalTrials.gov，NCT01067742，