Kummer Kai K, Kalpachidou Theodora, Kress Michaela, Langeslag Michiel
Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck, Austria.
Front Mol Neurosci. 2018 Jan 25;10:449. doi: 10.3389/fnmol.2017.00449. eCollection 2017.
Fabry disease is an X-linked lysosomal storage disorder with involvement of the nervous system. Accumulation of glycosphingolipids within peripheral nerves and/or dorsal root ganglia results in pain due to small-fiber neuropathy, which affects the majority of patients already in early childhood. The α-galactosidase A deficient mouse proved to be an adequate model for Fabry disease, as it shares many symptoms including altered temperature sensitivity and pain perception. To characterize the signatures of gene expression that might underlie Fabry disease-associated sensory deficits and pain, we performed one-color based hybridization microarray expression profiling of DRG explants from adult α-galactosidase A deficient mice and age-matched wildtype controls. Protein-protein interaction (PPI) and pathway analyses were performed for differentially regulated mRNAs. We found 812 differentially expressed genes between adult α-galactosidase A deficient mice and age-matched wildtype controls, 506 of them being upregulated, and 306 being downregulated. Among the enriched pathways and processes, the disease-specific pathways "lysosome" and "ceramide metabolic process" were identified, enhancing reliability of the current analysis. Novel pathways that we identified include "G-protein coupled receptor signaling" and "retrograde transport" for the upregulated genes. From the analysis of downregulated genes, immune-related pathways, autoimmune, and infection pathways emerged. The current analysis is the first to present a differential gene expression profile of DRGs from α-galactosidase A deficient mice, thereby providing knowledge on possible mechanisms underlying neuropathic pain related symptoms in Fabry patients. Therefore, the presented data provide new insights into the development of the pain phenotype and might lead to new treatment strategies.
法布里病是一种累及神经系统的X连锁溶酶体贮积症。糖鞘脂在周围神经和/或背根神经节内蓄积，导致小纤维神经病变引起疼痛，大多数患者在幼儿期就会受到影响。α-半乳糖苷酶A缺陷小鼠被证明是法布里病的合适模型，因为它具有许多共同症状，包括温度敏感性改变和疼痛感知异常。为了表征可能是法布里病相关感觉缺陷和疼痛基础的基因表达特征，我们对成年α-半乳糖苷酶A缺陷小鼠和年龄匹配的野生型对照的背根神经节外植体进行了基于单色杂交的微阵列表达谱分析。对差异调节的mRNA进行了蛋白质-蛋白质相互作用（PPI）和通路分析。我们发现成年α-半乳糖苷酶A缺陷小鼠和年龄匹配的野生型对照之间有812个差异表达基因，其中506个上调，306个下调。在富集的通路和过程中，鉴定出疾病特异性通路“溶酶体”和“神经酰胺代谢过程”，提高了当前分析的可靠性。我们鉴定出的新通路包括上调基因的“G蛋白偶联受体信号传导”和“逆行转运”。从下调基因的分析中，出现了免疫相关通路、自身免疫和感染通路。当前分析首次呈现了α-半乳糖苷酶A缺陷小鼠背根神经节的差异基因表达谱，从而提供了关于法布里病患者神经性疼痛相关症状潜在机制的知识。因此，所呈现的数据为疼痛表型的发展提供了新见解，并可能导致新的治疗策略。
