High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A
High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A
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DOI：
10.1038/cdd.2014.4
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发表时间：
2014-06-01
影响因子：
12.4
通讯作者：
Ledesma, M. D.
中科院分区：
文献类型：
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作者：
Gabande-Rodriguez, E.;Boya, P.;Ledesma, M. D.
A型尼曼匹克病（Niemann Pick disease type A，NPA）是由酸性鞘磷脂酶（ASM）基因的功能缺失突变引起的，是导致神经变性的溶酶体储存疾病。然而，溶酶体功能障碍及其在疾病中的后果的特点很差。在这里，我们表明，未降解的分子建立在神经元的酸性鞘磷脂酶基因敲除小鼠和成纤维细胞从NPA患者的自噬溶酶体积累。后者不是由于自噬起始或自噬体-溶酶体融合的改变，而是由于自噬-溶酶体清除效率低下。这又可以通过溶酶体膜透化导致组织蛋白酶B的胞质释放来解释。高鞘磷脂（SM）水平解释了这些效应，因为它们可以在添加脂质的对照细胞中诱导，并在ASM缺陷细胞中恢复SM降低策略。这些结果揭示了SM在自噬调节中的相关作用，并表征了NPA中的自噬异常，为治疗干预开辟了新的前景。
Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions.