title: Alkaptonuria is a novel human secondary amyloidogenic disease.
abstract: Alkaptonuria (AKU) is an ultra-rare disease developed from the lack of homogentisic acid oxidase activity, causing homogentisic acid (HGA) accumulation that produces a HGA-melanin ochronotic pigment, of unknown composition. There is no therapy for AKU. Our aim was to verify if AKU implied a secondary amyloidosis. Congo Red, Thioflavin-T staining and TEM were performed to assess amyloid presence in AKU specimens (cartilage, synovia, periumbelical fat, salivary gland) and in HGA-treated human chondrocytes and cartilage. SAA and SAP deposition was examined using immunofluorescence and their levels were evaluated in the patients' plasma by ELISA. 2D electrophoresis was undertaken in AKU cells to evaluate the levels of proteins involved in amyloidogenesis. AKU osteoarticular tissues contained SAA-amyloid in 7/7 patients. Ochronotic pigment and amyloid co-localized in AKU osteoarticular tissues. SAA and SAP composition of the deposits assessed secondary type of amyloidosis. High levels of SAA and SAP were found in AKU patients' plasma. Systemic amyloidosis was assessed by Congo Red staining of patients' abdominal fat and salivary gland. AKU is the second pathology after Parkinson's disease where amyloid is associated with a form of melanin. Aberrant expression of proteins involved in amyloidogenesis has been found in AKU cells. Our findings on alkaptonuria as a novel type II AA amyloidosis open new important perspectives for its therapy, since methotrexate treatment proved to significantly reduce in vitro HGA-induced A-amyloid aggregates.
authors: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Fiorentina 1, 53100 Siena, Italy.
authors: Lia
authors: L
authors: Millucci
authors: Adriano
authors: A
authors: Spreafico
authors: Laura
authors: L
authors: Tinti
authors: Daniela
authors: D
authors: Braconi
authors: Lorenzo
authors: L
authors: Ghezzi
authors: Eugenio
authors: E
authors: Paccagnini
authors: Giulia
authors: G
authors: Bernardini
authors: Loredana
authors: L
authors: Amato
authors: Marcella
authors: M
authors: Laschi
authors: Enrico
authors: E
authors: Selvi
authors: Mauro
authors: M
authors: Galeazzi
authors: Alessandro
authors: A
authors: Mannoni
authors: Maurizio
authors: M
authors: Benucci
authors: Pietro
authors: P
authors: Lupetti
authors: Federico
authors: F
authors: Chellini
authors: Maurizio
authors: M
authors: Orlandini
authors: Annalisa
authors: A
authors: Santucci
mesh_terms: D000368:Aged; D000474:Alkaptonuria / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000686:Amyloidosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D019902:Chondrocytes / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D050560:Homogentisate 1,2-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D006713:Homogentisic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D008543:Melanins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D000683:Serum Amyloid P-Component / Q000378:metabolism*; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism
chemical_list: D008543:Melanins; D000685:Serum Amyloid A Protein; D000683:Serum Amyloid P-Component; D050560:Homogentisate 1,2-Dioxygenase; D006713:Homogentisic Acid