Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration
Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration
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DOI：
10.1093/hmg/ddw025
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发表时间：
2016-04-01
影响因子：
3.5
通讯作者：
Lieberman, Andrew P.
中科院分区：
文献类型：
--
作者：
Chung, Chan;Puthanveetil, Prasanth;Lieberman, Andrew P.
尼曼-匹克C1（NPC）病是一种由NPC 1基因功能缺失突变引起的常染色体隐性遗传性脂质转运障碍，其特征是进行性神经变性，导致认知障碍、共济失调和早期死亡。关于导致神经元损失的细胞通路知之甚少。在这里，我们研究了半胱氨酸蛋白酶抑制剂B，组织蛋白酶B，H和L的内源性抑制剂的表达减少对NPC神经病理学发展的影响。我们发现，患者成纤维细胞中胱抑素B的表达降低可增强组织蛋白酶活性。Npc 1缺陷小鼠中编码Cstb基因的缺失导致显著的有害作用，特别是在小脑内，在年轻小鼠中观察到浦肯野细胞的弥漫性损失。这种严重的病理学通过触发浦肯野细胞死亡的细胞自主机制发生。此外，我们的分析表明，Npc 1缺陷的浦肯野细胞的胞质溶胶内的溶酶体组织蛋白酶的错误定位。我们提供的证据表明，这可能是由于活性氧（ROS）对溶酶体膜的损伤，导致溶酶体内容物的泄漏，最终导致凋亡性细胞死亡。与这一观点一致，在NPC细胞模型中，通过半胱氨酸蛋白酶抑制剂B的过表达或组织蛋白酶B的药理学抑制来减弱ROS的毒性。观察到Npc 1和Cstb缺失在遗传上相互作用，从而有效地增强了NPC小脑的退行性表型，这为溶酶体膜透化导致NPC疾病中小脑退行性变的观点提供了强有力的支持。
Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occurred through cell autonomous mechanisms that triggered Purkinje cell death. Moreover, our analyses demonstrated the mislocalization of lysosomal cathepsins within the cytosol of Npc1-deficient Purkinje cells. We provide evidence that this may be a consequence of damage to lysosomal membranes by reactive oxygen species (ROS), leading to the leakage of lysosomal contents that culminates in apoptotic cell death. Consistent with this notion, toxicity from ROS was attenuated in an NPC cell model by cystatin B over-expression or pharmacological inhibition of cathepsin B. The observation that Npc1 and Cstb deletion genetically interact to potently enhance the degenerative phenotype of the NPC cerebellum provides strong support for the notion that lysosomal membrane permeabilization contributes to cerebellar degeneration in NPC disease.