Cathepsin D deficiency delays central nervous system myelination by inhibiting proteolipid protein trafficking from late endosome/lysosome to plasma membrane.
Cathepsin D deficiency delays central nervous system myelination by inhibiting proteolipid protein trafficking from late endosome/lysosome to plasma membrane.
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组织蛋白酶 D 缺乏通过抑制蛋白脂质从晚期内体/溶酶体到质膜的运输来延迟中枢神经系统髓鞘形成
DOI：
10.1038/emm.2017.291
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发表时间：
2018-03-16
影响因子：
12.8
通讯作者：
Pan SY
中科院分区：
文献类型：
--
作者：
Guo DZ;Xiao L;Liu YJ;Shen C;Lou HF;Lv Y;Pan SY
本研究旨在探讨组织蛋白酶D在中枢神经系统髓鞘形成中的作用及其可能机制。采用基因敲除小鼠，结合免疫组织化学、免疫细胞化学和免疫印迹等方法，观察了体内、外中枢神经系统髓鞘形成和少突胶质细胞系细胞的发育情况。采用内吞实验、实时延时实验和全内反射荧光显微镜观察蛋白质脂蛋白在少突胶质细胞系细胞中的定位和运动。此外，还通过免疫沉淀法探讨了相关的分子机制。在P11、P14和P24龄时，CASTD−/−小鼠的胼胝体中的荧光髓鞘绿染色和蛋白脂蛋白的表达没有显著增加。蛋白脂蛋白在各时间点表达较弱，主要聚集在胞核周围。少突胶质细胞系细胞(OLIG2+)和成熟少突胶质细胞(CC1+)的数量在P14-P24期间显著减少。在−/−小鼠少突胶质前体细胞培养中，髓鞘碱性蛋白阳性的成熟少突胶质细胞形态简单，少突胶质前体细胞向成熟少突胶质细胞分化延迟。此外，更多的蛋白质脂蛋白聚集在晚期的内切体/溶酶体(LES/LS)中，较少的蛋白质到达质膜。免疫组织化学和免疫电子显微镜分析表明，在晚期内体/溶酶体中，caxD、蛋白脂蛋白和VAMP7可以相互结合，而VAMP7和Proteolipid蛋白与caxD共存。本论文的研究结果提示，caxD可能通过改变蛋白脂蛋白的转运，在中枢神经系统的髓鞘形成过程中发挥重要作用。
This study aimed to investigate the role of cathepsin D (CathD) in central nervous system (CNS) myelination and its possible mechanism. By using CathD knockout mice in conjunction with immunohistochemistry, immunocytochemistry and western blot assays, the myelination of the CNS and the development of oligodendrocyte lineage cells in vivo and in vitro were observed. Endocytosis assays, real-time-lapse experiments and total internal reflection fluorescence microscopy were used to demonstrate the location and movement of proteolipid protein in oligodendrocyte lineage cells. In addition, the relevant molecular mechanism was explored by immunoprecipitation. The increase in Fluoromyelin Green staining and proteolipid protein expression was not significant in the corpus callosum of CathD−/− mice at the age of P11, P14 and P24. Proteolipid protein expression was weak at each time point and was mostly accumulated around the nucleus. The number of oligodendrocyte lineage cells (olig2+) and mature oligodendrocytes (CC1+) significantly decreased between P14 and P24. In the oligodendrocyte precursor cell culture of CathD−/− mice, the morphology of myelin basic protein-positive mature oligodendrocytes was simple while oligodendrocyte precursor cells showed delayed differentiation into mature oligodendrocytes. Moreover, more proteolipid protein gathered in late endosomes/lysosomes (LEs/Ls) and fewer reached the plasma membrane. Immunohistochemistry and immunoelectron microscopy analysis showed that CathD, proteolipid protein and VAMP7 could bind with each other, whereas VAMP7 and proteolipid protein colocalized with CathD in late endosome/lysosome. The findings of this paper suggest that CathD may have an important role in the myelination of CNS, presumably by altering the trafficking of proteolipid protein.
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DOI：
10.1083/jcb.200202124
发表时间：
2002-08-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Edgar JM;Anderson TJ;Dickinson PJ;Barrie JA;McCulloch MC;Nave KA;Griffiths IR
通讯作者：
Griffiths IR
影响因子：
4.1
作者：
FUSEK, M;VETVICKA, V
通讯作者：
VETVICKA, V
影响因子：
5.3
作者：
Kippert, Angelika;Trajkovic, Katarina;Simons, Mikael
通讯作者：
Simons, Mikael
影响因子：
2.5
作者：
Haapanen, Aleksi;Ramadan, Usama Abo;Tyynelae, Jaana
通讯作者：
Tyynelae, Jaana
影响因子：
2.9
作者：
ENG, LF;CHAO, FC;TAVASTSTJERNA, MG
通讯作者：
TAVASTSTJERNA, MG