CLN6的管腔尾介导的CLN6突变体之间的功能干扰作为神经元类脂肪褐变的一种新的病理机制。

IF 1.3 4区 医学 Q4 MEDICINE, RESEARCH & EXPERIMENTAL
Yuki Shiro, Arisa Yamashita, Kana Watanabe, Tetsuo Yamazaki
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引用次数: 2

摘要

CLN6 (Ceroid Lipofuscinosis, Neuronal, 6)是一种横跨内质网膜的含有311个氨基酸的蛋白质。CLN6的突变与CLN6疾病有关,CLN6疾病是一种遗传性神经退行性疾病,被归类为神经元类脂褐质病。CLN6疾病是一种常染色体隐性遗传病,患有这种疾病的个体有两个相同(纯合)或两个不同(复合杂合)的CLN6突变等位基因。目前对CLN6的生理作用和发病机制知之甚少。我们最近发现CLN6阻止蛋白聚集形成,指出CLN6的抗聚集活性受损是导致该疾病的原因之一。为了全面了解其病理机制,考虑到患者对CLN6等位基因的复合杂合,需要研究两种不同CLN6突变体的总体抗聚集活性。我们专注于涉及S132CfsX18 (132fsX)过早终止蛋白的突变组合,该蛋白由CLN6中最常见的突变产生。132fsX突变体使P299L型CLN6错义突变体的抗聚集活性无效,而野生型CLN6的抗聚集活性无效。野生型CLN6对132fsX突变体的抗性通过用5个丙氨酸残基替换氨基酸297-301(包括Pro297和Pro299)而被消除。考虑到CLN6的c端15个氨基酸297-311 (luminal tail)的移除并未影响抗性,我们认为当CLN6的luminal tail从pro297 /299介导的构象约束中释放出来时,被132fsX突变体不正确定位,从而阻断了抗聚集活性的诱导。我们在此揭示了CLN6突变体残余功能耗散的新机制,为复合杂合驱动的发病机制提供了解释。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CLN6's luminal tail-mediated functional interference between CLN6 mutants as a novel pathomechanism for the neuronal ceroid lipofuscinoses.

CLN6 (Ceroid Lipofuscinosis, Neuronal, 6) is a 311-amino acid protein spanning the endoplasmic reticulum membrane. Mutations in CLN6 are linked to CLN6 disease, a hereditary neurodegenerative disorder categorized into the neuronal ceroid lipofuscinoses. CLN6 disease is an autosomal recessive disorder and individuals affected with this disease have two identical (homozygous) or two distinct (compound heterozygous) CLN6 mutant alleles. Little has been known about CLN6's physiological roles and the disease mechanism. We recently found that CLN6 prevents protein aggregate formation, pointing to impaired CLN6's anti-aggregate activity as a cause for the disease. To comprehensively understand the pathomechanism, overall anti-aggregate activity derived from two different CLN6 mutants needs to be investigated, considering patients compound heterozygous for CLN6 alleles. We focused on mutant combinations involving the S132CfsX18 (132fsX) prematurely terminated protein, produced from the most frequent mutation in CLN6. The 132fsX mutant nullified anti-aggregate activity of the P299L CLN6 missense mutant but not of wild-type CLN6. Wild-type CLN6's resistance to the 132fsX mutant was abolished by replacement of amino acids 297-301, including Pro297 and Pro299, with five alanine residues. Given that removal of CLN6's C-terminal fifteen amino acids 297-311 (luminal tail) did not affect the resistance, we suggested that CLN6's luminal tail, when unleashed from Pro297/299-mediated conformational constraints, is improperly positioned by the 132fsX mutant, thereby blocking the induction of anti- aggregate activity. We here reveal a novel mechanism for dissipating CLN6 mutants' residual functions, providing an explanation for the compound heterozygosity-driven pathogenesis.

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来源期刊
Biomedical Research-tokyo
Biomedical Research-tokyo 医学-医学:研究与实验
CiteScore
2.40
自引率
0.00%
发文量
19
审稿时长
>12 weeks
期刊介绍: Biomedical Research is peer-reviewed International Research Journal . It was first launched in 1990 as a biannual English Journal and later became triannual. From 2008 it is published in Jan-Apr/ May-Aug/ Sep-Dec..
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