Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis
Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis
复制标题
DOI：
10.1111/j.1471-4159.2008.05497.x
复制
发表时间：
2008-08-01
影响因子：
4.7
通讯作者：
Braulke, Thomas
中科院分区：
文献类型：
--
作者：
Jabs, Sabrina;Quitsch, Arne;Braulke, Thomas
神经元蜡样脂褐质病包括一组遗传性严重神经退行性溶酶体疾病，其特征是溶酶体功能障碍和荧光脂色素和聚集蛋白的大量积累。为了研究脂质在这些疾病的神经退行性过程中的作用，我们分别分析了 ctsd-/- 和 nclf 小鼠（组织蛋白酶 D 和 CLN6 缺乏的疾病模型）大脑中的磷酸脂和糖脂。 ctsd-/- 和 nclf 小鼠均表现出 GM2 和 GM3 神经节苷脂水平增加。免疫组织化学显示 GM2 和 GM3 染色分别优先出现在 ctsd-/- 小鼠的神经元和神经胶质细胞中。特别值得注意的是，在 ctsd-/- 小鼠的大脑中特别检测到异常的溶血磷脂双（单酰基甘油）磷酸增加了 20 倍，并伴随着不同细胞中未酯化胆固醇的零星积累。 ctsd-/- 小鼠大脑中鞘脂激活蛋白前体（一种体外组织蛋白酶 D 底物）的加工受损可能提供了与脂质储存的机制联系。这些研究首次表明组织蛋白酶 D 调节溶酶体磷酸鞘脂和糖鞘脂代谢，表明晚期内吞途径膜组分的组成、运输和/或再循环缺陷可能对于早发神经元蜡样脂褐质病的发病机制至关重要。
The neuronal ceroid lipofuscinoses comprise a group of inherited severe neurodegenerative lysosomal disorders characterized by lysosomal dysfunction and massive accumulation of fluorescent lipopigments and aggregated proteins. To examine the role of lipids in neurodegenerative processes of these diseases, we analysed phospho- and glycolipids in the brains of ctsd-/- and nclf mice, disease models of cathepsin D and CLN6 deficiency, respectively. Both ctsd-/- and nclf mice exhibited increased levels of GM2 and GM3 gangliosides. Immunohistochemically GM2 and GM3 staining was found preferentially in neurons and glial cells, respectively, of ctsd-/- mice. Of particular note, a 20-fold elevation of the unusual lysophospholipid bis(monoacylglycero)phosphate was specifically detected in the brain of ctsd-/- mice accompanied with sporadic accumulation of unesterified cholesterol in distinct cells. The impaired processing of the sphingolipid activator protein precursor, an in vitro cathepsin D substrate, in the brain of ctsd-/- mice may provide the mechanistic link to the storage of lipids. These studies show for the first time that cathepsin D regulates the lysosomal phospho- and glycosphingolipid metabolism suggesting that defects in the composition, trafficking and/or recycling of membrane components along the late endocytic pathway may be critical for the pathogenesis of early onset neuronal ceroid lipofuscinoses.