Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice.
Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice.
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DOI：
10.1186/2051-5960-2-20
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发表时间：
2014-02-14
影响因子：
7.1
通讯作者：
Shacka JJ
中科院分区：
文献类型：
--
作者：
Nelson MP;Tse TE;O'Quinn DB;Percival SM;Jaimes EA;Warnock DG;Shacka JJ
α-半乳糖苷酶 A 基因突变会导致法布里病，这是一种罕见的 X 连锁溶酶体贮积症，其特征是 α-半乳糖苷酶 A 酶活性丧失。由此产生的鞘糖脂在全身的积累会导致广泛的血管病变，尤其对肾脏、心脏和神经系统造成损害。先前已在法布里病中记录了自噬-溶酶体途径的破坏，但其对法布里病神经系统病理学的相对贡献尚不清楚。使用法布里病（α-半乳糖苷酶 A 缺乏症）实验小鼠模型，我们检查了 20-24 个月大小鼠的脑部病理学，特别强调自噬-溶酶体途径。 α-半乳糖苷酶 A 缺陷的小鼠大脑在几个脑区的实质中表现出增强的自噬标记物微管相关蛋白轻链 3 (LC3) 的点状核周免疫反应性，以及增强的溶酶体相关膜蛋白 1 (LAMP-1) 的实质和血管免疫反应性。超微结构分析揭示了具有电子密度的内皮细胞内含物和电子致密脂色素的明显积累。 α-半乳糖苷酶 A 缺陷小鼠的脑桥尤其表现出惊人的神经病理表型，包括存在表明轴突变性的大而肿胀的轴突球体，以及与轴突球体共定位的磷酸化 α-突触核蛋白阳性的大间质聚集体。双标记免疫荧光显示磷酸化 α-突触核蛋白聚集体与泛素和 LC3 的共定位。这些发现共同表明，α-半乳糖苷酶 A 缺陷小鼠大脑中广泛的神经病理学和集中的轴突神经变性与自噬-溶酶体途径的破坏有关，并为未来自噬-溶酶体途径对这种组织学表型的贡献进行机械评估提供了基础。本文的在线版本 (doi:10.1186/2051-5960-2-20) 包含补充材料，可供授权用户使用。
Mutations in the gene for alpha-galactosidase A result in Fabry disease, a rare, X-linked lysosomal storage disorder characterized by a loss of alpha-galactosidase A enzymatic activity. The resultant accumulation of glycosphingolipids throughout the body leads to widespread vasculopathy with particular detriment to the kidneys, heart and nervous system. Disruption in the autophagy-lysosome pathway has been documented previously in Fabry disease but its relative contribution to nervous system pathology in Fabry disease is unknown. Using an experimental mouse model of Fabry disease, alpha-galactosidase A deficiency, we examined brain pathology in 20-24 month old mice with particular emphasis on the autophagy-lysosome pathway. Alpha-galactosidase A-deficient mouse brains exhibited enhanced punctate perinuclear immunoreactivity for the autophagy marker microtubule-associated protein light-chain 3 (LC3) in the parenchyma of several brain regions, as well as enhanced parenchymal and vascular immunoreactivity for lysosome-associated membrane protein-1 (LAMP-1). Ultrastructural analysis revealed endothelial cell inclusions with electron densities and a pronounced accumulation of electron-dense lipopigment. The pons of alpha-galactosidase A-deficient mice in particular exhibited a striking neuropathological phenotype, including the presence of large, swollen axonal spheroids indicating axonal degeneration, in addition to large interstitial aggregates positive for phosphorylated alpha-synuclein that co-localized with the axonal spheroids. Double-label immunofluorescence revealed co-localization of phosphorylated alpha-synuclein aggregates with ubiquitin and LC3. Together these findings indicate widespread neuropathology and focused axonal neurodegeneration in alpha-galactosidase A-deficient mouse brain in association with disruption of the autophagy-lysosome pathway, and provide the basis for future mechanistic assessment of the contribution of the autophagy-lysosome pathway to this histologic phenotype. The online version of this article (doi:10.1186/2051-5960-2-20) contains supplementary material, which is available to authorized users.
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DOI：
10.1073/pnas.94.6.2540
发表时间：
1997-03-18
影响因子：
11.1
作者：
Ohshima, T;Murray, GJ;Kulkarni, AB
通讯作者：
Kulkarni, AB
影响因子：
2.8
作者：
Haertig, Wolfgang;Reichenbach, Andreas;Grosche, Jens
通讯作者：
Grosche, Jens
影响因子：
3.8
作者：
Moore, DF;Altarescu, G;Schiffmann, R
通讯作者：
Schiffmann, R
影响因子：
64.5
作者：
Mazzulli JR;Xu YH;Sun Y;Knight AL;McLean PJ;Caldwell GA;Sidransky E;Grabowski GA;Krainc D
通讯作者：
Krainc D
影响因子：
21.3
作者：
Fujiwara, H;Hasegawa, M;Iwatsubo, T
通讯作者：
Iwatsubo, T