Transglutaminase-catalyzed crosslinking in neurological disease: from experimental evidence to therapeutic inhibition.
Diseases of polyglutamine expansion, Alzheimer's disease and Parkinson's disease are neurodegenerative diseases associated with insoluble protein aggregates and neuronal death. These diseases constitute a group of devastating diseases for which there is currently little treatment. The protein aggregates may be the cause of neuronal death, although there is some controversy as to which form of aggregation (oligomers, polymers or microscopic aggregates) is the most toxic. More than a decade ago, the participation of transglutaminases in the formation of the abnormal protein aggregates was proposed. Transglutaminases are a large family of enzymes that catalyze the formation of N(sigma) (gamma-glutamyl)-lysine isodipeptide crosslinks between proteins. In this review, we summarize the evidence supporting the participation of transglutaminase in diseases of the central nervous system. We also describe newly developed transglutaminase inhibitors and their potential use as therapeutic agents in neurological disease.
Hoffner
G
G
UPR CNRS, Université Paris Descartes, France.
André
W
W
Vanhoutteghem
A
A
Souès
S
S
Djian
P
P
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D005973:Glutamine; D011503:Transglutaminases; C105804:transglutaminase 1