GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis
GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis
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DOI：
10.1016/j.molcel.2004.08.029
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发表时间：
2004-09-10
期刊：
影响因子：
16
通讯作者：
d'Azzo, A
中科院分区：
文献类型：
--
作者：
Tessitore, A;del P Martin, M;d'Azzo, A
G（M1）-神经节苷脂（G（M1））是神经元膜的主要唾液酸糖脂，其在其它功能中调节钙稳态。由于溶酶体β-半乳糖苷酶（β-gal）缺乏导致的Gm过度积累是神经退行性疾病G（M1）-神经节苷脂沉积症的特征，但G（M1）的积累是否直接导致CNS发病机制尚不清楚。在这里，我们证明了未折叠蛋白反应（UPR）的激活与BiP和CHOP的上调以及JNK 2和caspase-12的激活相关，导致G（M1）-神经节苷脂沉积症小鼠模型中的神经元凋亡。Gm，野生型神经球的负载重演了β-gal（-/-）细胞的表型，并通过耗尽ER钙储存激活该途径，最终导致细胞凋亡。在β-gal和神经节苷脂合酶β-gal（-/-）/GaINAcT-/-双缺陷小鼠中未发生UPR途径的激活，其不积累G（M1）。这些结果表明，UPR可以诱导唾液酸糖脂G（M1）的积累，这导致了一种新的神经元凋亡机制。
G(M1)-ganglioside (G(M1)) is a major sialoglycolipid of neuronal membranes that, among other functions, modulates calcium homeostasis. Excessive accumulation of Gm, due to deficiency of lysosomal beta-galactosidase (beta-gal) characterizes the neurodegenerative disease G(M1)-gangliosidosis, but whether the accumulation of G(M1) is directly responsible for CNS pathogenesis was unknown. Here we demonstrate that activation of an unfolded protein response (UPR) associated with the upregulation of BiP and CHOP and the activation of JNK2 and caspase-12 leads to neuronal apoptosis in the mouse model of G(M1)-gangliosidosis. Gm, loading of wild-type neurospheres recapitulated the phenotype of beta-gal(-/-) cells and activated this pathway by depleting ER calcium stores, which ultimately culminated in apoptosis. Activation of UPR pathways did not occur in mice double deficient for beta-gal and ganglioside synthase, beta-gal(-/-)/GaINAcT-/-, which do not accumulate G(M1). These findings suggest that the UPR can be induced by accumulation of the sialoglycolipid G(M1) and this causes a novel mechanism of neuronal apoptosis.