Implications of graded reductions in CLN6’s anti-aggregate activity for the development of the neuronal ceroid lipofuscinoses
Implications of graded reductions in CLN6’s anti-aggregate activity for the development of the neuronal ceroid lipofuscinoses
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CLN6 抗聚集活性逐步降低对神经元蜡样脂褐质沉积症发展的影响
DOI：
10.1016/j.bbrc.2020.03.019
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发表时间：
2020
影响因子：
3.1
通讯作者：
Yamazaki Tetsuo
中科院分区：
文献类型：
--
作者：
Yamashita Arisa;Shiro Yuki;Hiraki Yuri;Yujiri Takatoshi;Yamazaki Tetsuo
跨越内质网膜的CLN6是一种功能未知的蛋白质。CLN6基因突变与一种称为CLN6病的常染色体隐性遗传疾病有关，CLN6病被归类为一种神经元样脂褐质病（NCL）。由于缺乏关于CLN6所起生理作用的信息，CLN6疾病的发病机制仍然知之甚少。我们之前证明了CLN6具有阻止蛋白聚集形成的能力，因此假设CLN6抗聚集活性的丧失是CLN6疾病发展的基础。为了验证这一假设，我们缩小了对CLN6抗聚集活性至关重要的区域，并随后研究了该区域内的致病突变是否会减弱CLN6对四种易于聚集的α b -晶体蛋白（αBC）突变体的抗聚集活性。Arg106ProfsX截断的CLN6突变体不能阻止四个αBC突变体的聚集，这是在自然发生的婴儿晚期CLN6疾病小鼠模型中发现的CLN6突变体的人类对应体。相比之下，与成人发病的CLN6疾病相关的Arg149Cys和Arg149His CLN6突变体分别阻断了4个αBC突变体中的2个和全部αBC突变体的聚集，这表明CLN6的抗聚集活性是根据同一氨基酸位置的取代模式进行差异调节的。总之，我们在此提出CLN6抗聚集活性的分级降低控制了晚期婴儿和成人发病NCL的临床病程。
CLN6, spanning the endoplasmic reticulum membrane, is a protein of unknown function. Mutations in the CLN6 gene are linked to an autosomal recessively inherited disorder termed CLN6 disease, classified as a form of the neuronal ceroid lipofuscinoses (NCL). The pathogenesis of CLN6 disease remains poorly understood due to a lack of information about physiological roles CLN6 plays. We previously demonstrated that CLN6 has the ability to prevent protein aggregate formation, and thus hypothesized that the abrogation of CLN6’s anti-aggregate activity underlies the development of CLN6 disease. To test this hypothesis, we narrowed down the region vital for CLN6’s anti-aggregate activity, and subsequently investigated if pathogenic mutations within the region attenuate CLN6’s anti-aggregate activity toward four aggregation-prone αB-crystallin (αBC) mutants. None of the four αBC mutants was prevented from aggregating by the Arg106ProfsX truncated CLN6 mutant, the human counterpart of thenclfmutant identified in a naturally occurring mouse model of late infantile-onset CLN6 disease. In contrast, the Arg149Cys and the Arg149His CLN6 mutants, both associated with adult-onset CLN6 disease, blocked aggregation of two out of and all of the four αBC mutants, respectively, indicating that CLN6’s anti-aggregate activity is differentially modulated according to the substitution pattern at the same amino acid position. Collectively, we here propose that the graded reduction in CLN6’s anti-aggregate activity governs the clinical course of late infantile- and adult-onset NCL.