Therapeutic effects of cystamine in a murine model of Huntington's disease.
The precise cause of neuronal death in Huntington's disease (HD) is unknown. Proteolytic products of the huntingtin protein can contribute to toxic cellular aggregates that may be formed in part by tissue transglutaminase (Tgase). Tgase activity is increased in HD brain. Treatment in R6/2 transgenic HD mice, using the transglutaminase inhibitor cystamine, significantly extended survival, improved body weight and motor performance, and delayed the neuropathological sequela. Tgase activity and N(Sigma)-(gamma-L-glutamyl)-L-lysine (GGEL) levels were significantly altered in HD mice. Free GGEL, a specific biochemical marker of Tgase activity, was markedly elevated in the neocortex and caudate nucleus in HD patients. Both Tgase and GGEL immunoreactivities colocalized to huntingtin aggregates. Cystamine treatment normalized transglutaminase and GGEL levels in R6/2 mice. These findings are consistent with the hypothesis that transglutaminase activity may play a role in the pathogenesis of HD, and they identify cystamine as a potential therapeutic strategy for treating HD patients.
Dedeoglu
Alpaslan
A
Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, USA.
Kubilus
James K
JK
Jeitner
Thomas M
TM
Matson
Samantha A
SA
Bogdanov
Misha
M
Kowall
Neil W
NW
Matson
Wayne R
WR
Cooper
Arthur J L
AJ
Ratan
Rajiv R
RR
Beal
M Flint
MF
Hersch
Steven M
SM
Ferrante
Robert J
RJ
D000284:Administration, Oral; D000368:Aged; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D002421:Caudate Nucleus / Q000378:metabolism / Q000473:pathology; D003538:Cystamine / Q000627:therapeutic use*; D004151:Dipeptides / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015996:Survival Rate; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
D015415:Biomarkers; D004151:Dipeptides; D018696:Neuroprotective Agents; C001299:epsilon-(gamma-glutamyl)-lysine; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D003538:Cystamine