Transglutaminase 2 as a therapeutic target for neurological conditions

被引:17
作者
Keillor, Jeffrey W. [1 ]
Johnson, Gail V. W. [2 ]
机构
[1] Univ Ottawa, Dept Chem & Biomol Sci, Ottawa, ON, Canada
[2] Univ Rochester, Dept Anesthesiol & Perioperat Med, Rochester, NY 14620 USA
关键词
Transglutaminase; 2; neurodegenerative diseases; Alzheimer's disease; Huntington's disease; Parkinson's disease; multiple sclerosis; CNS injury; TG2; inhibitors; TISSUE-TYPE TRANSGLUTAMINASE; HUNTINGTONS-DISEASE; ALPHA-SYNUCLEIN; CROSS-LINKING; PARKINSONS-DISEASE; MESSENGER-RNA; MOUSE MODEL; IRREVERSIBLE INHIBITORS; SELECTIVE INHIBITORS; COVALENT INHIBITORS;
D O I
10.1080/14728222.2021.1989410
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Introduction: Transglutaminase 2 (TG2) has been implicated in numerous neurological conditions, including neurodegenerative diseases, multiple sclerosis, and CNS injury. Early studies on the role of TG2 in neurodegenerative conditions focused on its ability to 'crosslink' proteins into insoluble aggregates. However, more recent studies have suggested that this is unlikely to be the primary mechanism by which TG2 contributes to the pathogenic processes. Although the specific mechanisms by which TG2 is involved in neurological conditions have not been clearly defined, TG2 regulates numerous cellular processes through which it could contribute to a specific disease. Given the fact that TG2 is a stress-induced gene and elevated in disease or injury conditions, TG2 inhibitors may be useful neurotherapeutics. Areas covered: Overview of TG2 and different TG2 inhibitors. A brief review of TG2 in neurodegenerative diseases, multiple sclerosis and CNS injury and inhibitors that have been tested in different models. Database search: prior to 1 July 2021. Expert Opinion: Currently, it appears unlikely that inhibiting TG2 in the context of neurodegenerative diseases would be therapeutically advantageous. However, for multiple sclerosis and CNS injuries, TG2 inhibitors may have the potential to be therapeutically useful and thus there is rationale for their further development.
引用
收藏
页码:721 / 731
页数:11
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共 122 条
[1]  
ACHYUTHAN KE, 1987, J BIOL CHEM, V262, P1901
[2]   Structure-Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase [J].
Akbar, Abdullah ;
McNeil, Nicole M. R. ;
Albert, Marie R. ;
Ta, Viviane ;
Adhikary, Gautam ;
Bourgeois, Karine ;
Eckert, Richard L. ;
Keillor, Jeffiey W. .
JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (18) :7910-7927
[3]   Tissue trans glutaminase catalyzes the formation of alpha-synuclein crosslinks in Parkinson's disease [J].
Andringa, G ;
Lam, KY ;
Chegary, M ;
Wang, X ;
Chase, TN ;
Bennett, MC .
FASEB JOURNAL, 2004, 18 (03) :932-+
[4]   Cysteamine Protects Neurons from Mutant Huntingtin Toxicity [J].
Arbeza, Nicolas ;
Robya, Elaine ;
Akimov, Sergey ;
Eddings, Chelsy ;
Ren, Mark ;
Wang, Xiaofang ;
Ross, Christopher A. .
JOURNAL OF HUNTINGTONS DISEASE, 2019, 8 (02) :129-143
[5]   Protein aggregates in Huntington's disease [J].
Arrasate, Montserrat ;
Finkbeiner, Steven .
EXPERIMENTAL NEUROLOGY, 2012, 238 (01) :1-11
[6]   Recent advances in the development of tissue transglutaminase (TG2) inhibitors [J].
Badarau, E. ;
Collighan, R. J. ;
Griffin, M. .
AMINO ACIDS, 2013, 44 (01) :119-127
[7]   Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions [J].
Badarau, Eduard ;
Wang, Zhuo ;
Rathbone, Dan L. ;
Costanzi, Andrea ;
Thibault, Thomas ;
Murdoch, Colin E. ;
El Alaoui, Said ;
Bartkeviciute, Milda ;
Griffin, Martin .
CHEMISTRY & BIOLOGY, 2015, 22 (10) :1347-1361
[8]   Tissue transglutaminase contributes to disease progression in the R6/2 Huntington's disease mouse model via aggregate-independent mechanisms [J].
Bailey, CDC ;
Johnson, GVW .
JOURNAL OF NEUROCHEMISTRY, 2005, 92 (01) :83-92
[9]   The protective effects of cystamine in the R6/2 Huntington's disease mouse involve mechanisms other than the inhibition of tissue transglutaminase [J].
Bailey, Craig D. C. ;
Johnson, Gail V. W. .
NEUROBIOLOGY OF AGING, 2006, 27 (06) :871-879
[10]   Targeted Covalent Inhibitors for Drug Design [J].
Baillie, Thomas A. .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2016, 55 (43) :13408-13421