Homogentisic acid induces aggregation and fibrillation of amyloidogenic proteins.
Biochim Biophys Acta Gen Subj
; 1861(2): 135-146, 2017 Feb.
Article
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| MEDLINE
| ID: mdl-27865997
ABSTRACT
BACKGROUND:
Alkaptonuria (AKU) is an ultra-rare inborn error of metabolism characterized by homogentisic acid (HGA) accumulation due to a deficient activity of the homogentisate 1.2-dioxygenase (HGD) enzyme. This leads to the production of dark pigments that are deposited onto connective tissues, a condition named 'ochronosis' and whose mechanisms are not completely clear. Recently, the potential role of hitherto unidentified proteins in the ochronotic process was hypothesized, and the presence of Serum Amyloid A (SAA) in alkaptonuric tissues was reported, allowing the classification of AKU as a novel secondary amyloidosis.METHODS:
Gel electrophoresis, Western Blot, Congo Red-based assays and electron microscopy were used to investigate the effects of HGA on the aggregation and fibrillation propensity of amyloidogenic proteins and peptides [Aß(1-42), transthyretin, atrial natriuretic peptide, α-synuclein and SAA]. LC/MS and in silico analyses were undertaken to identify possible binding sites for HGA (or its oxidative metabolite, a benzoquinone acetate or BQA) in SAA.RESULTS:
We found that HGA might act as an amyloid aggregation enhancer in vitro for all the tested proteins and peptides in a time- and dose- dependent fashion, and identified a small crevice at the interface between two HGD subunits as a candidate binding site for HGA/BQA.CONCLUSIONS:
HGA might be an important amyloid co- component playing significant roles in AKU amyloidosis. GENERALSIGNIFICANCE:
Our results provide a possible explanation for the clinically verified onset of amyloidotic processes in AKU and might lay the basis to setup proper pharmacological approaches to alkaptonuric ochronosis, which are still lacking.Palabras clave
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Bases de datos:
MEDLINE
Asunto principal:
Proteínas Amiloidogénicas
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Agregación Patológica de Proteínas
/
Ácido Homogentísico
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Biochim Biophys Acta Gen Subj
Año:
2017
Tipo del documento:
Article
País de afiliación:
Italia