| Autor: |
Mastroeni P; ONE-HEALTH Lab, Department of Biotechnology, Chemistry and Pharmacy, University of Siena Via Aldo Moro, 53100 Siena, Italy., Trezza A; ONE-HEALTH Lab, Department of Biotechnology, Chemistry and Pharmacy, University of Siena Via Aldo Moro, 53100 Siena, Italy., Geminiani M; ONE-HEALTH Lab, Department of Biotechnology, Chemistry and Pharmacy, University of Siena Via Aldo Moro, 53100 Siena, Italy., Frusciante L; ONE-HEALTH Lab, Department of Biotechnology, Chemistry and Pharmacy, University of Siena Via Aldo Moro, 53100 Siena, Italy., Visibelli A; ONE-HEALTH Lab, Department of Biotechnology, Chemistry and Pharmacy, University of Siena Via Aldo Moro, 53100 Siena, Italy., Santucci A; ONE-HEALTH Lab, Department of Biotechnology, Chemistry and Pharmacy, University of Siena Via Aldo Moro, 53100 Siena, Italy.; MetabERN, Department of Biotechnology, Chemistry and Pharmacy, University of Siena Via Aldo Moro, 53100 Siena, Italy. |
| Abstrakt: |
Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene, leading to the accumulation of homogentisic acid (HGA), causing severe inflammatory conditions. Recently, the presence of serum amyloid A (SAA) has been reported in AKU tissues, classifying AKU as novel secondary amyloidosis; AA amyloidosis is characterized by the extracellular tissue deposition of fibrils composed of fragments of SAA. AA amyloidosis may complicate several chronic inflammatory conditions, like rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, chronic infections, neoplasms, etc. Treatments of AA amyloidosis relieve inflammatory disorders by reducing SAA concentrations; however, no definitive therapy is currently available. SAA regulation is a crucial step to improve AA secondary amyloidosis treatments. Here, applying a comprehensive in vitro and in silico approach, we provided evidence that HGA is a disruptor modulator of SAA, able to enhance its polymerization, fibril formation, and aggregation upon SAA/SAP colocalization. In silico studies deeply dissected the SAA misfolding molecular pathway and SAA/HGA binding, suggesting novel molecular insights about it. Our results could represent an important starting point for identifying novel therapeutic strategies in AKU and AA secondary amyloidosis-related diseases. |
