Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases encompass a heterogeneous group of disorders that afflict millions of people worldwide. Characteristic protein aggregates are histopathological hallmark features of these disorders, including Amyloid β (Aβ)-containing plaques and tau-containing neurofibrillary tangles in Alzheimer’s disease, α-Synuclein (α-Syn)-containing Lewy bodies and Lewy neurites in Parkinson’s disease and dementia with Lewy bodies, and mutant huntingtin (mHTT) in nuclear inclusions in Huntington’s disease. These various aggregates are found in specific brain regions that are impacted by neurodegeneration and associated with clinical manifestations. Transglutaminase (TG2) (also known as tissue transglutaminase) is the most ubiquitously expressed member of the transglutaminase family with protein crosslinking activity. To date, Aβ, tau, α-Syn, and mHTT have been determined to be substrates of TG2, leading to their aggregation and implicating the involvement of TG2 in several pathophysiological events in neurodegenerative disorders. In this review, we summarize the biochemistry and physiologic functions of TG2 and describe recent advances in the pathogenetic role of TG2 in these diseases. We also review TG2 inhibitors tested in clinical trials and discuss recent TG2-targeting approaches, which offer new perspectives for the design of future highly potent and selective drugs with improved brain delivery as a disease-modifying treatment for neurodegenerative disorders.

Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors

“…As described above, different molecular factors are able to induce TGM2 expression, such as RA and mediators of inflammation, and the mechanisms underlying their action have been widely investigated [51]. On the other hand, several examples of TG2 inhibitors have been reported, such as competitive amines and reversible and irreversible inhibitors, but their effects on TG2 pleiotropic functions are more complex to outline [11,92,94]. Representative inhibitors of TG2 are summarized in Table 1.…”

“…The role of TG2 in induction of apoptosis, resulting in neuronal degeneration, is well established [90][91][92]. Therefore, its involvement in neurodegenerative diseases was reported [93,94]. Moreover, TG2 acts as an inhibitor of autophagy progression.…”