Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transglutaminase type 2 (TG2) has recently been implicated in crosslinking of mutant huntingtin protein into aggregates. Here we show that TG2 also crosslinks spinocerebellar ataxia-1 (SCA1) gene product ataxin-1. HeLa cell lysates expressing GFP tagged ataxin-1 with 2, 30 or 82 glutamines showed covalent crosslinking of ataxin-1 when incubated with exogenously added TG2. This crosslinking was inhibited by TG2 inhibitor cystamine. SCA1 transgenic mice which overexpress the mutant ataxin-1 in cerebellar Purkinje cells showed elevated nuclear TG2 in the absence of ataxin-1 nuclear aggregates. The addition of purified TG2 to the nuclear extracts or addition of SCA1 nuclear TG2 to GFP-Q82 HeLa cell lysates resulted in the formation of insoluble aggregates. These data indicate that ataxin-1 is a substrate of TG2. Further, in SCA1 TG2 may translocate to the nucleus in response to nuclear accumulation of mutant ataxin-1 at early stages of the disease.
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PMID:Tissue transglutaminase crosslinks ataxin-1: possible role in SCA1 pathogenesis. 1704 96

Transglutaminase 2 (TG2) is well characterized as the main autoantigen of celiac disease. The ability of TG2 to deamidate and crosslink gluten peptides is essential for the gluten-dependent production of TG2 specific autoantibodies. In patients with primarily extraintestinal manifestation of gluten sensitivity the repertoire of autoantibodies may be different. In dermatitis herpetiformis (DH), TG3 appears to be the target autoantigen whereas in gluten ataxia (GA) autoantibodies reactive with TG6 are present. A functional role for TG3 and TG6 in these diseases has yet to be described. It is also not known whether these enzymes can use gluten peptides implicated in the pathology as substrates. We here report that similar to TG2, TG3 and TG6 can specifically deamidate gluten T cell epitopes. However, the fine specificities of the enzymes were found to differ. TG2 can form covalent complexes with gluten by iso-peptide and thioester bonds. We found that both TG3 and TG6 were able to complex with gluten peptides through thioester linkage although less efficiently than TG2, whereas TG6 but not TG3 was able to form iso-peptide linked complexes. Our findings lend credence to the notion that TG3 and TG6 are involved in the gluten-induced autoimmune responses of DH and GA.
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PMID:Gluten T cell epitope targeting by TG3 and TG6; implications for dermatitis herpetiformis and gluten ataxia. 2030 Jul 88

Transglutaminase (TG) is a kind of calcium-dependent enzymes. The TGase family found in rodents and human contains 9 types, including TG1-7, blood coagulation factor XIIIa and erythrocyte membrane protein 4.2, with the former 8 types possessing catalytic activity. TG catalyzes various conversion reactions of glutamine, including transamination, deamination and esterification, and participates in post-transcriptional modification of proteins such as cross-linking peptides glutamine residue and lysyl-residue, stabilizing protein structure and catalyzing formation of protein aggregates. TGase has been found to contribute to a variety of important physiological and pathological processes and play a role in the pathogenesis of multiple diseases. Notably, neurodegenerative diseases such as Huntington's disease, spinocerebellar ataxia, Alzheimer's disease and Parkinson's disease, have a close connection with TGase's role in the human body.
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PMID:[Transglutaminase and neurodegenerative diseases]. 2625 8

In humans, 9 members of the transglutaminase (TG) family have been identified, of which 8 [factor XIII (FXIII)A and TG1-TG7] catalyze post-translational protein-modifying reactions, and 1 does not (protein 4.2). The TG enzymatic activities considered in our discussion of human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. Except for TG7, which remains poorly studied, all individual TG members have been correlated with disparate human diseases that arise from either TG function or lack of function. Loss of TG function is associated with numerous orphan diseases that affect a relatively small number of individuals: loss of FXIIIa (transamidase-activated form) crosslinking leads to defects in blood coagulation in FXIII deficiency; loss of TG1 and TG5 cross linking leads to defects in epidermal cornification in lamellar ichthyosis and acral peeling skin syndrome, respectively; loss of TG3 crosslinking in hair-cuticle formation leads to uncombable hair syndrome; the predicted loss of TG6 crosslinking leads to spinocerebellar ataxia-35; and loss of the structural erythrocyte membrane protein, protein 4.2, leads to hereditary spherocytosis type 5. The enzymatic activity of TG2 is involved in the exacerbation of celiac disease and in at least 1 case of hemoglobinopathy, characterized by shortened erythrocyte lifespan. TGs are also autoantigens in a number of immune diseases, resulting in the production of autoantibodies against FXIIIa in acquired FXIII deficiency, TG2 in celiac disease, TG3 in dermatitis herpetiformis, TG4 in autoimmume polyglandular syndrome type 1, and TG6 in gluten axonal neuropathy and gluten ataxia. Much still remains to be learned and confirmed with respect to disease mechanisms, particularly with respect to TG-related immune diseases, in which development of isozyme-specific inhibitors may be useful for treatment.-Lorand, L., Iismaa, S. E. Transglutaminase diseases: from biochemistry to the bedside.
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PMID:Transglutaminase diseases: from biochemistry to the bedside. 3081 25