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.
Cells. 2024 Sep 7;13(17):1501. doi: 10.3390/cells13171501.
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.
尿黑酸尿症（AKU）是一种罕见的常染色体隐性遗传代谢疾病，由 HOMOGENTISATE 1,2-双加氧酶（HGD）基因突变引起，导致 HOMOGENTISIC 酸（HGA）积累，引起严重的炎症状态。最近，在 AKU 组织中发现了血清淀粉样蛋白 A（SAA）的存在，将 AKU 归类为新型继发性淀粉样变性；AA 淀粉样变性的特征是由 SAA 片段组成的纤维在细胞外组织中沉积。AA 淀粉样变性可能使几种慢性炎症性疾病复杂化，如类风湿关节炎、强直性脊柱炎、炎症性肠病、慢性感染、肿瘤等。AA 淀粉样变性的治疗通过降低 SAA 浓度来缓解炎症性疾病；然而，目前尚无明确的治疗方法。SAA 调节是改善 AA 继发性淀粉样变性治疗的关键步骤。在这里，我们应用了全面的体外和计算方法，提供了证据表明 HGA 是 SAA 的破坏调节剂，能够增强其聚合、纤维形成和聚集，当 SAA/SAP 共定位时。计算研究深入剖析了 SAA 错误折叠的分子途径和 SAA/HGA 结合，提出了关于它的新的分子见解。我们的研究结果可能为确定 AKU 和 AA 继发性淀粉样变性相关疾病的新治疗策略提供了一个重要的起点。
