title: Transglutaminase inhibition protects against oxidative stress-induced neuronal death downstream of pathological ERK activation.
abstract: Molecular deletion of transglutaminase 2 (TG2) has been shown to improve function and survival in a host of neurological conditions including stroke, Huntington's disease, and Parkinson's disease. However, unifying schemes by which these cross-linking or polyaminating enzymes participate broadly in neuronal death have yet to be presented. Unexpectedly, we found that in addition to TG2, TG1 gene expression level is significantly induced following stroke in vivo or due to oxidative stress in vitro. Forced expression of TG1 or TG2 proteins is sufficient to induce neuronal death in Rattus norvegicus cortical neurons in vitro. Accordingly, molecular deletion of TG2 alone is insufficient to protect Mus musculus neurons from oxidative death. By contrast, structurally diverse inhibitors used at concentrations that inhibit TG1 and TG2 simultaneously are neuroprotective. These small molecules inhibit increases in neuronal transamidating activity induced by oxidative stress; they also protect neurons downstream of pathological ERK activation when added well after the onset of the death stimulus. Together, these studies suggest that multiple TG isoforms, not only TG2, participate in oxidative stress-induced cell death signaling; and that isoform nonselective inhibitors of TG will be most efficacious in combating oxidative death in neurological disorders.
authors.affiliation: Winifred Masterson Burke Medical Research Institute, White Plains, NY 10605, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Basso
authors.forename: Jill
authors.initials: J
authors.lastname: Berlin
authors.forename: Li
authors.initials: L
authors.lastname: Xia
authors.forename: Sama F
authors.initials: SF
authors.lastname: Sleiman
authors.forename: Brendan
authors.initials: B
authors.lastname: Ko
authors.forename: Renee
authors.initials: R
authors.lastname: Haskew-Layton
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.forename: Marc A
authors.initials: MA
authors.lastname: Antonyak
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
authors.forename: Siiri E
authors.initials: SE
authors.lastname: Iismaa
authors.forename: Dianna
authors.initials: D
authors.lastname: Willis
authors.forename: Sunghee
authors.initials: S
authors.lastname: Cho
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency
chemical_list: D018696:Neuroprotective Agents; C000717609:Tgm2 protein, rat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C105804:transglutaminase 1; D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins