Abnormal Accumulation of tTGase Products in Muscle and Erythrocytes of Chorea-Acanthocytosis Patients

• Published in: Journal of neuropathology and experimental neurology 2002-10, Vol.61 (10), p.841-848
• Main Authors: MELONE, MARIAROSA A.B, DI FEDE, GIUSEPPE, PELUSO, GIANFRANCO, LUS, GIACOMO, DI IORIO, GIUSEPPE, SAMPAOLO, SIMONE, CAPASSO, ANTONIO, GENTILE, VITTORIO, COTRUFO, ROBERTO
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Chorea - blood; Chorea - enzymology; Chorea - pathology; Cross-Linking Reagents; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Erythrocytes - enzymology; Erythrocytes - pathology; Erythrocytes - ultrastructure; GTP-Binding Proteins - blood; GTP-Binding Proteins - metabolism; Humans; Isoenzymes - blood; Isoenzymes - metabolism; Medical sciences; Microscopy, Electron; Muscle, Skeletal - enzymology; Muscle, Skeletal - pathology; Muscle, Skeletal - ultrastructure; Neurology; Peptide Mapping; Transglutaminases - blood; Transglutaminases - metabolism
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/61.10.841

Chorea-Acanthocytosis (CHAC) is an autosomal recessive disease characterized by neurodegeneration and acanthocytosis. Enhanced creatine kinase concentration is a constant feature of the condition. The mechanism underlying CHAC is unknown. However, acanthocytosis and enhanced creatine kinase suggest a protein defect that deranges the membrane-cytoskeleton interface in erythrocytes and muscle, thereby resulting in neurodegeneration. Acanthocytes have been correlated with structural and functional changes in membrane protein band 3—a ubiquitous anion transporter. Residue Gln-30 of band 3 serves as a membrane substrate for tissue transglutaminase (tTGase), which belongs to a class of intra- and extra-cellular Ca-dependent cross-linking enzymes found in most vertebrate tissues. In an attempt to cast light on the pathophysiology of CHAC, we used reverse-phase HPLC and immunohistochemistry to evaluate the role of tTGase in this disorder. We found increased amounts of tTGase-derived N-(-γ-glutamyl)lysine isopeptide cross-links in erythrocytes and muscle from CHAC patients. Furthermore, immunohistochemistry demonstrated abnormal accumulation of tTGase products as well as proteinaceous bodies in CHAC muscles. These findings could explain the mechanisms underlying the increased blood levels of creatine kinase and acanthocytosis, which are the most consistent features of this neurodegenerative disease.