Zaguri Dor, Shaham-Niv Shira, Naaman Efrat, Mimouni Michael, Magen Daniella, Pollack Shirley, Kreiser Topaz, Leibu Rina, Rencus-Lazar Sigal, Adler-Abramovich Lihi, Perlman Ido, Gazit Ehud, Zayit-Soudry Shiri
School of Molecular Cell Biology & Biotechnology, Tel Aviv University, Tel Aviv, 69978, Israel.
Blavatnik Center for Drug Discovery, Metabolite Medicine Division, Tel Aviv University, Tel Aviv, 6997801, Israel.
Commun Chem. 2020 Jan 3;3(1):2. doi: 10.1038/s42004-019-0247-8.
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.
代谢物纤维状聚集体的形成代表了人类代谢紊乱研究中的范式转变。然而，直接的临床相关性仅归因于代谢物晶体。代谢物结晶的一个显著例子是在包括原发性高草酸尿症在内的各种疾病中观察到的草酸钙晶体。我们意外地在没有晶体的年轻高草酸尿症患者中观察到视网膜损伤。为了探索可能形成的替代性超分子组织及其生物学作用，我们在此表明，草酸盐可以形成不伴有钙的有序纤维。这些纤维在培养细胞中造成强烈的视网膜细胞毒性。注射草酸盐纤维的大鼠模型重现了在患者中观察到的视网膜功能障碍模式。从高草酸尿症患者血清中纯化的抗体能够识别草酸盐纤维，而与钙的存在无关。这些发现突出了草酸盐相关疾病的新分子基础，并且据我们所知，为代谢物纤维状聚集体的致病作用提供了首个直接临床指征。
