Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
JCI Insight. 2018 Mar 22;3(6):99171. doi: 10.1172/jci.insight.99171.
Fabry disease, the most common lysosomal storage disease, affects multiple organs and results in a shortened life span. This disease is caused by a deficiency of the lysosomal enzyme α-galactosidase A, which leads to glycosphingolipid accumulation in many cell types. Neuropathic pain is an early and severely debilitating symptom in patients with Fabry disease, but the cellular and molecular mechanisms that cause the pain are unknown. We generated a rat model of Fabry disease, the first nonmouse model to our knowledge. Fabry rats had substantial serum and tissue accumulation of α-galactosyl glycosphingolipids and had pronounced mechanical pain behavior. Additionally, Fabry rat dorsal root ganglia displayed global N-glycan alterations, sensory neurons were laden with inclusions, and sensory neuron somata exhibited prominent sensitization to mechanical force. We found that the cation channel transient receptor potential ankyrin 1 (TRPA1) is sensitized in Fabry rat sensory neurons and that TRPA1 antagonism reversed the behavioral mechanical sensitization. This study points toward TRPA1 as a potentially novel target to treat the pain experienced by patients with Fabry disease.
法布瑞氏病，最常见的溶酶体贮积病，影响多个器官，并导致寿命缩短。这种疾病是由于溶酶体酶α-半乳糖苷酶 A 的缺乏引起的，导致许多细胞类型中糖鞘脂的积累。神经病理性疼痛是法布瑞氏病患者的早期和严重致残症状，但导致疼痛的细胞和分子机制尚不清楚。我们生成了法布瑞氏病的大鼠模型，这是我们所知的第一个非小鼠模型。法布瑞氏病大鼠的血清和组织中有大量的α-半乳糖基神经酰胺积累，并有明显的机械性疼痛行为。此外，法布瑞氏病大鼠背根神经节显示出全球 N-聚糖改变，感觉神经元充满包含物，感觉神经元胞体对机械力表现出明显的敏化。我们发现，阳离子通道瞬时受体电位锚蛋白 1（TRPA1）在法布瑞氏病大鼠感觉神经元中被敏化，而 TRPA1 拮抗剂逆转了行为性机械敏化。这项研究表明，TRPA1 可能是治疗法布瑞氏病患者疼痛的一个新的潜在靶点。
