Possible involvement of transglutaminase-catalyzed reactions in the physiopathology of neurodegenerative diseases
- First Online:
- Cite this article as:
- Martin, A., Giuliano, A., Collaro, D. et al. Amino Acids (2013) 44: 111. doi:10.1007/s00726-011-1081-1
- 282 Views
Transglutaminases are ubiquitous enzymes, which catalyze post-translational modifications of proteins. Recently, transglutaminases and tranglutaminase-catalyzed post-translational modification of proteins have been shown to be involved in the molecular mechanisms responsible for several human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for human neurodegenerative diseases. Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, supranuclear palsy, Huntington’s disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. In this review, we focus on the possible molecular mechanisms by which transglutaminase activity could be involved in the pathogenesis of neurodegenerative diseases, and on the possible therapeutic effects of selective transglutaminase inhibitors for the cure of patients with diseases characterized by aberrant transglutaminase activity.
KeywordsTransglutaminasesPost-translational modifications of proteinsNervous SystemNeurodegenerative diseases
Transglutaminases (E.C. 18.104.22.168; TGs) are a family of related and ubiquitous enzymes, which catalyze post-translational modifications of proteins. These enzymes are also capable of catalyzing other reactions important for cell life. The distribution and the physiological roles of TGs have been widely studied in numerous cell types and tissues, and recently their roles in human diseases have begun to be identified. For example, the transglutaminase activity has been hypothesized to be involved in the pathogenetic mechanisms responsible for several human diseases, including neurodegenerative diseases. A recent wide range of studies has already clearly shown that the “tissue” transglutaminase (tTG or TG 2) is responsible for a very widespread human pathology, Celiac Disease (CD). This disease is due to intolerance to a food protein, gliadin, and is characterized by a very complex clinical syndrome, which includes gastrointestinal pathological manifestations, often associated with extra-intestinal manifestations. Interestingly, a subset of celiac patients develops neurological disorders. In this review, we describe the possible roles played by TGs in molecular mechanisms, which could be responsible for the physiopathology of neurodegenerative diseases.
Biochemistry of the transglutaminases
Transglutaminases and their biological roles when known
TG 1 (Keratinocyte TG, kTG)
TG 2 (Tissue TG, tTG, cTG)
Apoptosis, cell adhesion, signal transduction
TG 3 (Epidermal TG, eTG)
Hair follicle differentiation
TG 4 (Prostate TG, pTG)
Suppression of sperm immunogenicity
TG 5 (TG X)
TG 6 (TG Y)
TG 7 (TG Z)
Molecular biology of the transglutaminases
Bioinformatic studies have shown that the primary structures of human TGs share some identities in only few regions, such as the active site and the calcium binding regions. However, high sequence conservation and, therefore, a high degree of preservation of residue secondary structure among TG2, TG3 and FXIIIa indicate that these TGs all share four-domain tertiary structures which could be similar to those of other TGs (Lorand and Graham 2003).
Transglutaminases and neurodegenerative diseases
Transglutaminases as potential therapeutic targets of neurodegenerative diseases
Although many scientific reports have implicated aberrant transglutaminase activity in the pathogenesis of neurodegenerative diseases, still today we are looking for data which could definitely confirm the direct involvement of TGs in the pathogenetic mechanisms responsible for these diseases. The use of inhibitors of TGs could be then useful for therapeutical approaches. To minimize the possible side effects, however, selective inhibitors of the TGs should be required in the future. Progress in this area of research may be achieved also through pharmaco-genetic techniques.
This work is supported by the Italian Education Department.
Conflict of interest
The authors declare that they have no conflict of interest.