Redox proteomics gives insights into the role of oxidative stress in alkaptonuria

Abstract

Alkaptonuria (AKU) is an ultra-rare metabolic disorder of the catabolic pathway of tyrosine and phenylalanine that has been poorly characterized at molecular level. As a genetic disease, AKU is present at birth, but its most severe manifestations are delayed due to the deposition of a dark-brown pigment (ochronosis) in connective tissues. The reasons for such a delayed manifestation have not been clarified yet, though several lines of evidence suggest that the metabolite accumulated in AKU sufferers (homogentisic acid) is prone to auto-oxidation and induction of oxidative stress. The clarification of the pathophysiological molecular mechanisms of AKU would allow a better understanding of the disease, help find a cure for AKU and provide a model for more common rheumatic diseases. With this aim, we have shown how proteomics and redox proteomics might successfully overcome the difficulties of studying a rare disease such as AKU and the limitations of the hitherto adopted approaches.

Keywords::

• antioxidants
• cartilage
• joints
• homogentisic acid
• ochronosis
• protein oxidation
• rare diseases

Financial & competing interests disclosure

This work was supported by Telethon Italy grant GGP10058. The authors thank AimAKU (Associazione Italiana Malati di Alcaptonuria, ORPHA263402), Toscana Life Sciences Orphan_1 project and Fonda-zione Monte dei Paschi di Siena. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Physio-pathology of alkaptonuria is still obscure.

• • No genotype-phenotype relationship apparently exists in alkaptonuria, making post-genomics mandatory.

• • Oxidative stress plays a fundamental role in physiopathology of ochronosis and alkaptonuria-related amyloidosis.

• • Human alkaptonuria serum-, cell- and tissue-based models have been set up.

• • Proteomics and redox-proteomics of alkaptonuria cells and serum models revealed strong homogentisic acid (HGA)-induced protein oxidation.

• • Carbonylation, thiol oxidation and benzoquinone acetate-binding are the main HGA-induced protein modifications observed.

• • HGA-induced structural/functional modifications are mainly directed toward proteins with a role in folding, metal homeostasis, response to stress (mainly oxidative) or functioning as carriers; some of them are involved in amyloidogenic processes.

• • These proteins may be considered molecular hallmarks of alkaptonuria and may provide the basis of an ‘oxidative-stress signature’ of the disease.

Notes