Sikora Jakub, Dworski Shaalee, Jones E Ellen, Kamani Mustafa A, Micsenyi Matthew C, Sawada Tomo, Le Faouder Pauline, Bertrand-Michel Justine, Dupuy Aude, Dunn Christopher K, Xuan Ingrid Cong Yang, Casas Josefina, Fabrias Gemma, Hampson David R, Levade Thierry, Drake Richard R, Medin Jeffrey A, Walkley Steven U
Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York; Institute of Inherited Metabolic Disorders, Charles University, 1st Faculty of Medicine, Prague, Czech Republic; Institute of Pathology, Charles University, 1st Faculty of Medicine, Prague, Czech Republic.
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Am J Pathol. 2017 Apr;187(4):864-883. doi: 10.1016/j.ajpath.2016.12.005.
Farber disease is a rare autosomal recessive disorder caused by acid ceramidase deficiency that usually presents as early-onset progressive visceral and neurologic disease. To understand the neurologic abnormality, we investigated behavioral, biochemical, and cellular abnormalities in the central nervous system of Asah1 mice, which serve as a model of Farber disease. Behaviorally, the mutant mice had reduced voluntary locomotion and exploration, increased thigmotaxis, abnormal spectra of basic behavioral activities, impaired muscle grip strength, and defects in motor coordination. A few mutant mice developed hydrocephalus. Mass spectrometry revealed elevations of ceramides, hydroxy-ceramides, dihydroceramides, sphingosine, dihexosylceramides, and monosialodihexosylganglioside in the brain. The highest accumulation was in hydroxy-ceramides. Storage compound distribution was analyzed by mass spectrometry imaging and morphologic analyses and revealed involvement of a wide range of central nervous system cell types (eg, neurons, endothelial cells, and choroid plexus cells), most notably microglia and/or macrophages. Coalescing and mostly perivascular granuloma-like accumulations of storage-laden CD68 microglia and/or macrophages were seen as early as 3 weeks of age and located preferentially in white matter, periventricular zones, and meninges. Neurodegeneration was also evident in specific cerebral areas in late disease. Overall, our central nervous system studies in Asah1 mice substantially extend the understanding of human Farber disease and suggest that this model can be used to advance therapeutic approaches for this currently untreatable disorder.
法伯病是一种罕见的常染色体隐性疾病，由酸性神经酰胺酶缺乏引起，通常表现为早发性进行性内脏和神经系统疾病。为了解神经系统异常情况，我们研究了作为法伯病模型的Asah1小鼠中枢神经系统中的行为、生化和细胞异常。在行为方面，突变小鼠的自主运动和探索减少、趋触性增加、基本行为活动谱异常、肌肉握力受损以及运动协调缺陷。少数突变小鼠出现脑积水。质谱分析显示大脑中神经酰胺、羟基神经酰胺、二氢神经酰胺、鞘氨醇、二己糖神经酰胺和单唾液酸二己糖神经节苷脂升高。最高蓄积物是羟基神经酰胺。通过质谱成像和形态学分析对储存化合物分布进行分析，结果显示多种中枢神经系统细胞类型（如神经元、内皮细胞和脉络丛细胞）均有累及，最显著的是小胶质细胞和/或巨噬细胞。早在3周龄时就可见到充满储存物的CD68小胶质细胞和/或巨噬细胞聚合并形成主要位于血管周围的肉芽肿样积聚，且优先位于白质、脑室周围区域和脑膜。在疾病后期，特定脑区也出现神经退行性变。总体而言，我们对Asah1小鼠中枢神经系统的研究极大地扩展了对人类法伯病的认识，并表明该模型可用于推进针对这种目前无法治疗的疾病的治疗方法。
