Anja Schulze-Krebs

Mammalian transglutaminases (TGs) catalyze calcium-dependent irreversible posttranslational modifications of proteins and their enzymatic activities contribute to the pathogenesis of several human neurodegenerative diseases. Although different transglutaminases are found in many different tissues, the TG6 isoform is mostly expressed in the CNS. The present study was embarked on/undertaken to investigate expression, distribution and activity of transglutaminases in Huntington disease transgenic rodent models, with a focus on analyzing the involvement of TG6 in the age- and genotype-specific pathological features relating to disease progression in HD transgenic mice and a tgHD transgenic rat model using biochemical, histological and functional assays. Our results demonstrate the physical interaction between TG6 and (mutant) huntingtin by co-immunoprecipitation analysis and the contribution of its enzymatic activity for the total aggregate load in SH-SY5Y cells. In addition, we identify that TG6 expression and activity are especially abundant in the olfactory tubercle and piriform cortex, the regions displaying the highest amount of mHTT aggregates in transgenic rodent models of HD. Furthermore, mHTT aggregates were colocalized within TG6-positive cells. These findings point towards a role of TG6 in disease pathogenesis via mHTT aggregate formation.

Patients with celiac disease display autoantibodies against tissue transglutaminase (TG2), and the high sensitivity and specificity of these autoantibodies render them a reliable tool for diagnosis. However, we found that denatured sera from healthy persons also showed reactivity against TG2. To further examine the specificity of this phenomenon, sera of healthy individuals and celiac patients were denatured by heat or pH shift. Denatured sera of all individuals showed autoantibodies against TG2 in ELISA that could be specifically inhibited by TG2, but the biological role of these autoantibodies remains unknown. The alpha fibrinogen precursor could be isolated as serum protein that reacts with TG2 antibodies and treated sera reacted with fibrinogen in Western blotting. Cross-reactivity of TG2 antibodies with fibrinogen and vice versa was observed. We hypothesise that denaturation of sera reveals hidden autoantibodies against TG2, which might be normally masked by fibrinogen.