Communications Chemistry ( IF 5.9 ) Pub Date : 2020-01-03 , DOI: 10.1038/s42004-019-0247-8 Dor Zaguri 1 , Shira Shaham-Niv 1, 2 , Efrat Naaman 3 , Michael Mimouni 3, 4 , Daniella Magen 4, 5 , Shirley Pollack 5 , Topaz Kreiser 1 , Rina Leibu 3 , Sigal Rencus-Lazar 1 , Lihi Adler-Abramovich 6 , Ido Perlman 4 , Ehud Gazit 1, 7 , Shiri Zayit-Soudry 3, 4
The formation of metabolite fibrillar assemblies represents a paradigm shift in the study of human metabolic disorders. Yet, direct clinical relevance has been attributed only to metabolite crystals. A notable example for metabolite crystallization is calcium oxalate crystals observed in various diseases, including primary hyperoxaluria. We unexpectedly observed retinal damage among young hyperoxaluria patients in the absence of crystals. Exploring the possible formation of alternative supramolecular organizations and their biological role, here we show that oxalate can form ordered fibrils with no associated calcium. These fibrils inflict intense retinal cytotoxicity in cultured cells. A rat model injected with oxalate fibrils recaptures patterns of retinal dysfunction observed in patients. Antibodies purified from hyperoxaluria patient sera recognize oxalate fibrils regardless of the presence of calcium. These findings highlight a new molecular basis for oxalate-associated disease, and to our knowledge provide the first direct clinical indication for the pathogenic role of metabolite fibrillar assemblies.
中文翻译:
纤维状草酸盐组装诱导视网膜病变
代谢物纤维状组装体的形成代表了人类代谢紊乱研究的范式转变。然而,直接的临床相关性仅归因于代谢物晶体。代谢物结晶的一个值得注意的例子是在各种疾病中观察到的草酸钙晶体,包括原发性高草酸尿症。我们出乎意料地观察到年轻的高草酸尿症患者在没有晶体的情况下会出现视网膜损伤。探索替代超分子组织的可能形成及其生物学作用,在这里我们表明草酸盐可以形成有序的原纤维而没有相关的钙。这些原纤维在培养的细胞中造成强烈的视网膜细胞毒性。注射草酸盐原纤维的大鼠模型重现了在患者身上观察到的视网膜功能障碍模式。无论是否存在钙,从高草酸尿症患者血清中纯化的抗体都能识别草酸盐原纤维。这些发现突出了草酸盐相关疾病的新分子基础,据我们所知,为代谢物原纤维组装体的致病作用提供了第一个直接的临床指示。