Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target.
Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target.
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DOI：
10.1038/cddis.2016.16
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发表时间：
2016-03-17
影响因子：
9
通讯作者：
Porter FD
中科院分区：
文献类型：
--
作者：
Cougnoux A;Cluzeau C;Mitra S;Li R;Williams I;Burkert K;Xu X;Wassif CA;Zheng W;Porter FD
尼曼-匹克病C1型（NPC1）是一种由NPC1基因突变引起的神经退行性溶酶体贮积性疾病。NPC1表型的特征是进行性神经元功能障碍，包括小脑性共济失调和痴呆。组织学证据显示神经炎症和进行性神经元丧失，小脑浦肯野细胞特别容易受到NPC1功能丧失的影响。坏死下垂被认为是神经元丧失的一种机制。受体相互作用蛋白激酶1 （RIP1）和RIP3是调节坏死性细胞死亡的坏死体复合体的关键成分。我们报道了RIP1和RIP3在NPC1小鼠和患者的成纤维细胞、NPC1 iPS细胞衍生的神经元前体以及小脑组织中的表达增加。我们的数据表明NPC1神经系统疾病的严重程度与坏死复合体的组装呈正相关。此外，我们证明了RIP1的药理抑制在体外和体内都可以减少细胞死亡。用坏死他汀-1 （RIP1的变抗抑制剂）治疗npc1突变小鼠，可显著延缓小脑浦肯野细胞的丢失、神经症状的进展和死亡。总的来说，我们的数据确定坏死性上睑下垂是导致NPC1神经元丢失的分子网络的关键组成部分，并确定抑制坏死性上睑下垂是一种潜在的治疗干预措施。
Niemann–Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention.