Insufficient ER-stress response causes selective mouse cerebellar granule cell degeneration resembling that seen in congenital disorders of glycosylation.
Insufficient ER-stress response causes selective mouse cerebellar granule cell degeneration resembling that seen in congenital disorders of glycosylation.
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DOI：
10.1186/1756-6606-6-52
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发表时间：
2013-12-04
期刊：
影响因子：
3.6
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Sun L;Zhao Y;Zhou K;Freeze HH;Zhang YW;Xu H
先天性糖基化障碍（CDG）是由糖基化缺陷引起的遗传性疾病。不正确的糖基化蛋白质诱导蛋白质错误折叠和内质网（ER）应激。CDG的最常见形式PMM 2-CDG是由胞质酶磷酸甘露糖变位酶2（PMM 2）的缺乏引起的。PMM 2-CDG患者小脑浦肯野细胞和颗粒细胞数量显著减少。然而，PMM 2-CDG中特定小脑神经变性的分子机制仍然是难以捉摸的。在此，我们报告，小脑颗粒细胞（CGCs）更敏感的衣霉素（TM）诱导的抑制总N-聚糖合成比皮质神经元（CN）。当聚糖合成受到类似程度的抑制时，CGC的细胞死亡率高于氯化萘。此外，PMM 2的下调导致更多的CGC死亡，而不是氯化萘。重要的是，我们发现，PMM 2下调或TM治疗后，ER应激反应蛋白在CGCs中的升高不太显著，而在CN中，GRP 78/BiP水平显示出最显著的差异。我们进一步证明GRP 78/BiP的过表达挽救了由TM处理或PMM 2下调引起的CGC死亡。我们的研究结果表明，小脑神经元对N-糖基化缺陷的选择性易感性是由于这些神经元对ER应激的反应效率低下，为CDG患者中观察到的选择性神经变性机制提供了重要的见解。
Congenital disorders of glycosylation (CDGs) are inherited diseases caused by glycosylation defects. Incorrectly glycosylated proteins induce protein misfolding and endoplasmic reticulum (ER) stress. The most common form of CDG, PMM2-CDG, is caused by deficiency in the cytosolic enzyme phosphomannomutase 2 (PMM2). Patients with PMM2-CDG exhibit a significantly reduced number of cerebellar Purkinje cells and granule cells. The molecular mechanism underlying the specific cerebellar neurodegeneration in PMM2-CDG, however, remains elusive. Herein, we report that cerebellar granule cells (CGCs) are more sensitive to tunicamycin (TM)-induced inhibition of total N-glycan synthesis than cortical neurons (CNs). When glycan synthesis was inhibited to a comparable degree, CGCs exhibited more cell death than CNs. Furthermore, downregulation of PMM2 caused more CGCs to die than CNs. Importantly, we found that upon PMM2 downregulation or TM treatment, ER-stress response proteins were elevated less significantly in CGCs than in CNs, with the GRP78/BiP level showing the most significant difference. We further demonstrate that overexpression of GRP78/BiP rescues the death of CGCs resulting from either TM-treatment or PMM2 downregulation. Our results indicate that the selective susceptibility of cerebellar neurons to N-glycosylation defects is due to these neurons’ inefficient response to ER stress, providing important insight into the mechanisms of selective neurodegeneration observed in CDG patients.
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