Metabolite Amyloids in Human Disease: Oxalate Nanofibrils Induce Comparable Retinopathy in Hyperoxaluria Patients and Treated Animals

Abstract

Purpose : The pathology of primary hyperoxaluria, characterized by abnormal oxalate accumulation with subsequent multi-organ dysfunction, has been attributed to the formation of calcium oxalate crystals leading to cellular injury. Here, we present the surprising observation of retinal damage among young patients in the absence of retinal crystals, thus challenging the generality of this accepted mechanism of oxalate crystal-related toxicity.

Methods : We explored the possible formation of alternative supramolecular oxalate organizations and their potential pathological role.

Results : We discovered that oxalate could form ordered fibrils possessing properties similar to those of proteinaceous amyloids. Unlike the canonical oxalate crystals, the formed nanofibrils did not contain calcium. The self-assembled fibrils inflicted cytotoxicity in cultured retinal pigment epithelial cells, as well as retinal toxicity in rats. Notably, wild-type rat eyes treated with the assemblies remarkably recaptured the patterns of retinal dysfunction observed in patients, thus establishing an in vivo model for the oxalate fibrils associated toxicity. The fibrils inflicted a glial response in treated rat eyes, reflected by their internalization into activated retinal Müller cells. Moreover, oxalate fibrils were recognized by antibodies from patient sera, providing further evidence for the occurrence of these assemblies in the disease state.

Conclusions : Taken together, these findings highlight a new molecular basis for oxalate-associated disease, potentially leading to the development of novel therapeutic avenues for these devastating conditions. Furthermore, our findings provide the first direct clinical indication for the pathogenic role of metabolite-amyloids in human error of metabolism disorders.

This is a 2020 ARVO Annual Meeting abstract.