A20 A role for transglutaminase 6 in hd pathology

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BackgroundMammalian transglutaminases (TGs) catalyze calcium-dependent irreversible post-translational modifications of proteins. In the nervous system, at least four different transglutaminase isoforms are found with TG6 representing the neuronal isoform. Their enzymatic activities contribute to the pathogenesis of several human neurodegenerative diseases.AimsThe present study was outlined to investigate expression, distribution and activity of transglutaminases, especially TG6, in Huntington´s disease rodent models.Methods/techniquesTo analyze the involvement of TG6 in the age- and genotype-specific pathological progressions in rodent HD animal models, protein, histological and functional assays were used.Results/outcomeWe demonstrate the physical interaction between TG6 and (mutant) huntingtin by co-immunoprecipitation analysis. In addition, we describe that TG6 expression and activity were especially abundant in the olfactory tubercle and piriform cortex, the regions displaying the highest amount of mHTT aggregates in HD transgenic rats. Furthermore, mHTT aggregates were found within TG6-positive cells.ConclusionsOur data strongly suggest a prominent role for TG6 in the post-translational modification of (m)HTT thus pointing away from TG2, so far being investigated most frequently. Our results suggest that TG6 activity on mHTT may be causative for the modification of mHTT fragments that would result to be more prone to aggregation. Furthermore, the aggregation process seems to depend more on the regional distribution and physical proximity of transglutaminases and mHTT, rather than on differences in total protein amounts. Further studies analyzing the impact of TG6 knock-out/inactivation on mHTT aggregation and disease progression will finally elucidate the pathological relevance of our findings.

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