Amyloid Mimicking Assemblies of Homogentisic Acid, N-Acetyl Aspartic Acid and Isovaleric Acid and its Implications in associated Rare Metabolic Diseases

Herein, we have studied the self-assembling and aggregation properties of Homogentisic acid (HA), N-acetyl aspartic Acid (NAA) and Isovaleric acid (IVA) with the aim to understand the effect of aggregation of these metabolites on the toxicities associated with rare metabolic diseases caused by their accumulation. To our surprise, we noted aggregation of HA, NAA and IVA follow amyloidogenic pathway and as these metabolites are aged small globules tend to merge and form fibrillar aggregates. These assemblies were characterized by conventional microscopy tools and their amyloidogenic nature was assessed by Thioflavin T binding assays. The cytotoxicity analysis by MTT assay suggest cellular viability was decreased in presence of metabolites in a dose dependent manner implicating their cytotoxic nature. Hence, the results presented in the manuscript are of significant interest as they can be of great practical implications in understanding the etiology/pathophysiology of rare metabolic diseases caused by the accumulation of these metabolites namely Alkaptonuria, Canavan diseases and Isovaleric academia from an amyloid perspective and may have possible implications in its therapeutic cure in future.