Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons.
Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons.
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DOI：
10.1016/s0168-0102(00)81020-2
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发表时间：
2000
期刊：
影响因子：
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通讯作者：
M. Koike;H. Nakanishi;P. Saftig;J. Ezaki;K. Isahara;Y. Ohsawa;W. Schulz-Schaeffer;T. Watanabe-T.-Wat
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文献类型：
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作者：
M. Koike;H. Nakanishi;P. Saftig;J. Ezaki;K. Isahara;Y. Ohsawa;W. Schulz-Schaeffer;T. Watanabe-T.-Wat
组织蛋白酶d缺陷（CD−/−）小鼠在接近终末期时表现为癫痫发作并失明[大约在出生后(P) 26]。因此，我们检测了这些小鼠中枢神经系统组织的形态学、免疫细胞化学和生化特征。通过电镜观察，P20后CD - / -小鼠大脑神经核周可见含有部分细胞质的自噬体/自溶体样体、颗粒状亲锇沉积物和指纹图谱。在P0时神经元中检测到自噬体和颗粒状嗜锇沉积物，但数量较少，而在出生后数天内神经元核周细胞中细胞数量增加。在P17时，在中枢神经系统组织中，特别是在丘脑区和大脑皮层中出现了一些核周围具有自噬体/自溶体样体的大尺寸神经元。这些溶酶体占据CD - / -小鼠大脑中几乎所有神经元的核周，从P23到终末期。由于这些神经元表现出自身荧光，我们认为蜡质脂褐素可能积聚在CD−/−神经元的溶酶体结构中。发现线粒体ATP合成酶c亚基在神经元溶酶体中积累，尽管脑内三肽基肽酶i的活性显著增加。此外，接近终末期的神经元经常萎缩，细胞核不规则，密集的小染色质团块分散在细胞核中。这些结果表明，CD - / -小鼠的CNS神经元表现出一种新的溶酶体堆积病，其表型类似于神经元类蜡质脂褐质病。
Cathepsin D-deficient (CD−/−) mice have been shown to manifest seizures and become blind near the terminal stage [approximately postnatal day (P) 26]. We therefore examined the morphological, immunocytochemical, and biochemical features of CNS tissues of these mice. By electron microscopy, autophagosome/autolysosome-like bodies containing part of the cytoplasm, granular osmiophilic deposits, and fingerprint profiles were demonstrated in the neuronal perikarya of CD−/− mouse brains after P20. Autophagosomes and granular osmiophilic deposits were detected in neurons at P0 but were few in number, whereas they increased in the neuronal perikarya within days after birth. Some large-sized neurons having autophagosome/autolysosome-like bodies in the perikarya appeared in the CNS tissues, especially in the thalamic region and the cerebral cortex, at P17. These lysosomal bodies occupied the perikarya of almost all neurons in CD−/− mouse brains obtained from P23 until the terminal stage. Because these neurons exhibited autofluorescence, it was considered that ceroid lipofuscin may accumulate in lysosomal structures of CD−/− neurons. Subunit c of mitochondrial ATP synthase was found to accumulate in the lysosomes of neurons, although the activity of tripeptidyl peptidase-I significantly increased in the brain. Moreover, neurons near the terminal stage were often shrunken and possessed irregular nuclei through which small dense chromatin masses were scattered. These results suggest that the CNS neurons in CD−/− mice show a new form of lysosomal accumulation disease with a phenotype resembling neuronal ceroid lipofuscinosis.