Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease)
Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease)
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DOI：
10.1016/s0002-9440(10)61253-9
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发表时间：
2005-12-01
影响因子：
6
通讯作者：
Uchiyama, Y
中科院分区：
文献类型：
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作者：
Koike, M;Shibata, M;Uchiyama, Y
在组织蛋白酶D缺陷(CD-/-)和组织蛋白酶B和L双缺陷(CB-/-CL-/-)小鼠中，异常的空泡结构聚集在脑神经元中。其中许多结构类似于自噬小体，其中保留了部分细胞质，但其确切的性质和生物发生尚不清楚。在这里，我们通过证明MAP1-Lc3的分子形式从胞液形式(Lc3-I)到膜结合形式(Lc3-II)的增加，展示了自噬如何在缺乏组织蛋白酶D或两者都缺乏组织蛋白酶B和L的神经元中促进这些空泡结构的积累。在CD-/-和CB-/-CL-/-小鼠脑中，免疫荧光显微镜和冷冻断裂免疫电子显微镜证实，在CD-/-和CB-/-CL-/-小鼠脑中，LC3-II以膜结合形式为主，而MAP1-LC3信号聚集在位于神经元核膜和轴突的颗粒结构中，定位于自噬体膜。此外，与CD-/-神经元一样，Cb-/-CL-/-神经元中也有自发荧光和线粒体ATP合成酶c亚单位的积累。这表明，不仅CD-/-小鼠，而且CB-/-CL-/-小鼠都可以作为神经元性蜡样脂褐素沉着症/巴顿病的动物模型。这些数据有力地证明了自噬在巴顿病/溶酶体储存障碍的发病机制中发挥了重要作用。
In cathepsin D-deficient (CD-/-) and cathepsins B and L double-deficient (CB-/-CL-/-) mice, abnormal vacuolar structures accumulate in neurons of the brains. Many of these structures resemble autophagosomes in which part of the cytoplasm is retained but their precise nature and biogenesis remain unknown. We show here how autophagy contributes to the accumulation of these vacuolar structures in neurons deficient in cathepsin D or both cathepsins B and L by demonstrating an increased conversion of the molecular form of MAP1-LC3 for autophagosome formation from the cytosolic form (LC3-I) to the membrane-bound form (LC3-II). in both CD-/- and CB-/-CL-/- mouse brains, the membrane-bound LC3-II form predominated whereas MAP1-LC3 signals accumulated in granular structures located in neuronal perikarya and axons of these mutant brains and were localized to the membranes of autophagosomes, evidenced by immunofluorescence microscopy and freeze-fracture-replica immunoelectron microscopy. Moreover, as in CD-/- neurons, autofluorescence and subunit c of mitochondrial ATP synthase accumulated in CB-/-CL-/- neurons. This suggests that not only CD-/- but also CB-/-CL-/- mice could be useful animal models for neuronal ceroid-lipofuscinosis/Batten disease. These data strongly argue for a major involvement of autophagy in the pathogenesis of Batten disease/lysosomal storage disorders.