Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease
Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease
复制标题
DOI：
10.1096/fj.07-102715
复制
发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Zanlungo, Silvana
中科院分区：
文献类型：
--
作者：
Alvarez, Alejandra R.;Klein, Andres;Zanlungo, Silvana
C型尼曼-匹克病（Niemann-Pick type C，NPC）是一种致死性的常染色体隐性遗传疾病，其特征是游离胆固醇和鞘糖脂在核内体-溶酶体系统中的积聚。NPC患者有明显的进行性神经元丢失，主要是小脑浦肯野神经元。有强有力的证据表明，胆固醇积累和运输缺陷激活NPC脑细胞凋亡。本研究的目的是分析细胞凋亡，特别是促凋亡c-Abl/p73系统在鼻咽癌小脑神经元变性中的相关性。我们使用NPC 1小鼠模型来评估c-Abl/p73在小脑中的表达和激活以及用c-Abl特异性抑制剂伊马替尼治疗的效果。鼻咽癌小鼠小脑中存在促凋亡c-Abl/p73系统和p73靶基因的表达。此外，伊马替尼抑制c-Abl可以保护浦肯野神经元，减少小脑中的一般细胞凋亡，改善神经症状，并增加NPC小鼠的存活率。此外，这种促存活作用与p73促凋亡靶基因的mRNA水平降低相关。我们的研究结果表明，c-Abl/p73通路参与了NPC神经退行性变，并表明用c-Abl抑制剂治疗可用于延迟进行性神经退行性变，支持使用伊马替尼临床治疗NPC疾病患者。
Niemann-Pick type C (NPC) disease is a fatal autosomal recessive disorder characterized by the accumulation of free cholesterol and glycosphingo-lipids in the endosomal-lysosomal system. Patients with NPC disease have markedly progressive neuronal loss, mainly of cerebellar Purkinje neurons. There is strong evidence indicating that cholesterol accumulation and trafficking defects activate apoptosis in NPC brains. The purpose of this study was to analyze the relevance of apoptosis and particularly the proapoptotic c-Abl/p73 system in cerebellar neuron degeneration in NPC disease. We used the NPC1 mouse model to evaluate c-Abl/p73 expression and activation in the cerebellum and the effect of therapy with the c-Abl-specific inhibitor imatinib. The proapoptotic c-Abl/p73 system and the p73 target genes are expressed in the cerebellums of NPC mice. Furthermore, inhibition of c-Abl with imatinib preserved Purkinje neurons and reduced general cell apoptosis in the cerebellum, improved neurological symptoms, and increased the survival of NPC mice. Moreover, this prosurvival effect correlated with reduced mRNA levels of p73 proapoptotic target genes. Our results suggest that the c-Abl/p73 pathway is involved in NPC neurodegeneration and show that treatment with c-Abl inhibitors is useful in delaying progressive neurodegeneration, supporting the use of imatinib for clinical treatment of patients with NPC disease.