Amyloid properties of the leader peptide of variant B cystatin C: implications for Alzheimer and macular degeneration
Amyloid properties of the leader peptide of variant B cystatin C: implications for Alzheimer and macular degeneration
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DOI：
10.1002/1873-3468.12093
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发表时间：
2016-03-01
期刊：
影响因子：
3.5
通讯作者：
Foguel, Debora
中科院分区：
文献类型：
--
作者：
Sant'Anna, Ricardo;Navarro, Susanna;Foguel, Debora
胱抑素C的变异体B(VB)的信号肽(A25T)发生突变，干扰其加工，导致分泌减少，部分滞留在线粒体附近。有遗传学证据表明VB与阿尔茨海默病(AD)和老年性黄斑变性(AMD)有关。在这里，我们结合计算和体外研究，研究了未加工的VB的聚集性和淀粉样蛋白倾向。聚集预测因子揭示了四个聚集倾向区域的存在，其中一个在信号肽水平上很强，它确实在溶液中形成了有毒的聚集体和成熟的淀粉样纤维。根据这些结果，我们首次提出了信号肽在AD和AMD发病机制中的作用。
Variant B (VB) of cystatin C has a mutation in its signal peptide (A25T), which interferes with its processing leading to reduced secretion and partial retention in the vicinity of the mitochondria. There are genetic evidences of the association of VB with Alzheimer's disease (AD) and age-related macular degeneration (AMD). Here, we investigated aggregation and amyloid propensities of unprocessed VB combining computational and in vitro studies. Aggregation predictors revealed the presence of four aggregation-prone regions, with a strong one at the level of the signal peptide, which indeed formed toxic aggregates and mature amyloid fibrils in solution. In light of these results, we propose for the first time the role of the signal peptide in pathogenesis of AD and AMD.