Homogentisic acid induces aggregation and fibrillation of amyloidogenic proteins

Inflammatory and oxidative stress biomarkers in alkaptonuria: data from the DevelopAKUre project

“…Control of the acute phase response is currently the standard of care in amyloidosis and rheumatic disorders 34,86 . This is also relevant in view of the recent in vitro reports indicating that even nearly physiological HGA concentrations might enhance the aggregation of SAA 62 . Importantly, all the data obtained within this work could be used to populate an AKU database integrating biomarker levels, demographics, patient's quality of life, environmental and life-style data, and clinical outcomes 82 .…”

“…There is an intimate connection between HGA, the ochronotic process, SAA and amyloidosis, inflammation and oxidative stress in AKU 7e10, 39,42,62,63 , demonstrated also by structural co-localization of ochronotic pigment and SAA-amyloid 10 and co-localization of SAA with crucial cytoskeletal proteins in AKU chondrocytes 64 . Mechanisms of ochronosis and pigment toxicity in AKU are not fully clear, but possible factors include the co-presence of amyloidosis and angiogenesis in tissues 12,42,65 and the oxidative and inflammatory effects of HGA on tissues and cells 8,14,17,19,20,42,63 .…”

“…We found that SAA serum levels were falling within a wide range in the tested AKU subjects. This becomes particularly relevant in the light of a recent work where HGA was found to act as an amyloid aggregation enhancer in vitro (in a time-and dosedependent fashion) for amyloidogenic proteins and peptides 62 . As the pro-aggregating effect of HGA towards SAA was found even at nearly physiological HGA concentrations in vitro 62 , pharmacological control of SAA circulating levels in AKU seems appropriate to be suggested, although such previous results were obtained with a recombinant protein and need further validation with wild-type SAA.…”

Seeding of proteins into amyloid structures by metabolite assemblies may clarify certain unexplained epidemiological associations

“…Another observation was the accelerated aggregation of a soluble mixture of amino acids following the addition of phenylalanine fibrils [ 23 ]. Additional study demonstrated the cross-seeding of proteins by homogentisic acid (HGA), a metabolite related to alkaptonuria [ 24 ], a rare IEM disorder which was lately classified as secondary amyloidosis. Alkaptonuria is characterized by the accumulation of HGA due to deficiency of homogentisate 1.2-dioxygenase enzyme ( figure 1 , table 1 ).…”

Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease—A review

“…Amyloidosis involves the conversion of normally soluble proteins into insoluble fibrillar aggregate structures. A growing literature suggests that it is a secondary effect of ochronosis in vitro and in vivo . A number of observations report presence of amyloid A protein aggregates and fibrils in AKU serum and ochronotic tissue from a number of locations including cartilage, synovia, heart, periumbrical abdominal, articular fat, and labial salivary gland.…”