ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones
ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones
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DOI：
10.1093/hmg/ddm324
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发表时间：
2008-02-14
影响因子：
3.5
通讯作者：
Mukherjee, Anil B.
中科院分区：
文献类型：
--
作者：
Wei, Hui;Kim, Sung-Jo;Mukherjee, Anil B.
据估计，超过40种不同的溶酶体贮积症（LSD）累积影响5000例活产中的1例，并且在大多数LSD中，神经变性是一个突出特征。神经元蜡样质脂褐质沉积症（NCL）作为一组，代表了最常见的（每12500例出生中有1例）神经退行性LSD。婴儿NCL（INCL）是最具破坏性的神经退行性LSD，其由棕榈酰蛋白硫酯酶-1（PPT 1）基因的失活突变引起。我们以前报道过INCL和模拟INCL的PPT 1敲除（PPT 1-KO）小鼠中细胞凋亡导致的神经元死亡至少部分是由内质网（ER）和氧化应激引起的。在本研究中，我们试图确定ER和氧化应激是INCL的独特表现，还是神经退行性和非神经退行性LSD的共同表现。出乎意料的是，我们发现ER和氧化应激是神经退行性和非神经退行性LSD细胞中的常见表现。此外，所有研究的LSD细胞对布雷菲德菌素A诱导的细胞凋亡表现出非凡的敏感性，这表明预先存在的ER应激条件。此外，我们发现正常细胞中溶酶体稳态的化学破坏导致ER应激，这表明溶酶体和ER之间存在串扰。最重要的是，我们发现，化学分子伴侣，减轻ER和氧化应激也细胞保护在所有形式的LSD研究。我们提出，ER和氧化应激是神经退行性和非神经退行性LSD细胞凋亡的共同介质，并建议化学/药理学分子伴侣的有益作用，至少部分地，通过减轻这些压力条件。
It is estimated that more than 40 different lysosomal storage disorders (LSDs) cumulatively affect one in 5000 live births, and in the majority of the LSDs, neurodegeneration is a prominent feature. Neuronal ceroid lipofuscinoses (NCLs), as a group, represent one of the most common (one in 12 500 births) neurodegenerative LSDs. The infantile NCL (INCL) is the most devastating neurodegenerative LSD, which is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. We previously reported that neuronal death by apoptosis in INCL, and in the PPT1-knockout (PPT1-KO) mice that mimic INCL, is at least in part caused by endoplasmic reticulum (ER) and oxidative stresses. In the present study, we sought to determine whether ER and oxidative stresses are unique manifestations of INCL or they are common to both neurodegenerative and non-neurodegenerative LSDs. Unexpectedly, we found that ER and oxidative stresses are common manifestations in cells from both neurodegenerative and non-neurodegenerative LSDs. Moreover, all LSD cells studied show extraordinary sensitivity to brefeldin-A-induced apoptosis, which suggests pre-existing ER stress conditions. Further, we uncovered that chemical disruption of lysosomal homeostasis in normal cells causes ER stress, suggesting a cross-talk between the lysosomes and the ER. Most importantly, we found that chemical chaperones that alleviate ER and oxidative stresses are also cytoprotective in all forms of LSDs studied. We propose that ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative LSDs and suggest that the beneficial effects of chemical/pharmacological chaperones are exerted, at least in part, by alleviating these stress conditions.