Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke
Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke
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DOI：
10.1093/hmg/ddt418
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发表时间：
2014-01-15
影响因子：
3.5
通讯作者：
Van Agtmael, Tom
中科院分区：
文献类型：
--
作者：
Murray, Lydia S.;Lu, Yinhui;Van Agtmael, Tom
出血性中风占中风病例的20%，而脑穿孔是围产期脑出血的临床后果。在这里，我们报告了在一个外显性降低的多孔性脑畸形家系中发现了COL4A2胶原域(胶原IVα链2)中的一个新的显性G702D突变。COL4A2是COL4A1必需的蛋白质伙伴，但与大多数COL4A1突变不同的是，COL4A2突变不会导致眼睛或肾脏疾病。对一名患者和他未受影响的父亲的真皮活检分析显示，两人都显示出基底膜(BM)缺陷。有趣的是，IV型胶原进入真皮BM的缺陷仅见于患者，并与原代真皮成纤维细胞中COL4A2的内质网(ER)滞留有关。这种细胞内堆积导致内质网应激，未折叠蛋白反应激活，细胞增殖减少，细胞凋亡增加。有趣的是，COL4A2在未受影响的父亲的细胞中没有内质网滞留和内质网应激，这表明突变的COL4A2从内质网中积累和/或清除可能是疾病发展的关键修饰物。我们的分析还表明，突变的IV型胶原是通过蛋白酶体降解的。重要的是，用化学伴侣处理患者细胞可以降低细胞内COL4A2水平、内质网应激和细胞凋亡，表明减少细胞内胶原积累可以改善COL4A2突变的细胞表型。重要的是，这些数据强调，操纵伴侣水平、细胞内胶原堆积和内质网应激是包括出血性中风在内的IV型胶原疾病的潜在治疗选择。
Haemorrhagic stroke accounts for similar to 20% of stroke cases and porencephaly is a clinical consequence of perinatal cerebral haemorrhaging. Here, we report the identification of a novel dominant G702D mutation in the collagen domain of COL4A2 (collagen IV alpha chain 2) in a family displaying porencephaly with reduced penetrance. COL4A2 is the obligatory protein partner of COL4A1 but in contrast to most COL4A1 mutations, the COL4A2 mutation does not lead to eye or kidney disease. Analysis of dermal biopsies from a patient and his unaffected father, who also carries the mutation, revealed that both display basement membrane(BM) defects. Intriguingly, defective collagen IV incorporation into the dermal BM was observed in the patient only and was associated with endoplasmic reticulum (ER) retention of COL4A2 in primary dermal fibroblasts. This intracellular accumulation led to ER stress, unfolded protein response activation, reduced cell proliferation and increased apoptosis. Interestingly, the absence of ER retention of COL4A2 and ER stress in cells from the unaffected father indicate that accumulation and/or clearance of mutant COL4A2 from the ER may be a critical modifier for disease development. Our analysis also revealed that mutant collagen IV is degraded via the proteasome. Importantly, treatment of patient cells with a chemical chaperone decreased intracellular COL4A2 levels, ER stress and apoptosis, demonstrating that reducing intracellular collagen accumulation can ameliorate the cellular phenotype of COL4A2 mutations. Importantly, these data highlight that manipulation of chaperone levels, intracellular collagen accumulation and ER stress are potential therapeutic options for collagen IV diseases including haemorrhagic stroke.