title: Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease.
abstract: Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-1alpha and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration.
authors.affiliation: Burke Medical Research Institute, White Plains, NY, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McConoughey
authors.forename: Manuela
authors.initials: M
authors.lastname: Basso
authors.forename: Zoya V
authors.initials: ZV
authors.lastname: Niatsetskaya
authors.forename: Sama F
authors.initials: SF
authors.lastname: Sleiman
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Smirnova
authors.forename: Brett C
authors.initials: BC
authors.lastname: Langley
authors.forename: Lata
authors.initials: L
authors.lastname: Mahishi
authors.forename: Arthur J L
authors.initials: AJ
authors.lastname: Cooper
authors.forename: Marc A
authors.initials: MA
authors.lastname: Antonyak
authors.forename: Rick A
authors.initials: RA
authors.lastname: Cerione
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Anatoly
authors.initials: A
authors.lastname: Starkov
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Chaturvedi
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Li
authors.initials: L
authors.lastname: Xia
authors.forename: Siiri E
authors.initials: SE
authors.lastname: Iismaa
authors.forename: Judit
authors.initials: J
authors.lastname: Pallos
authors.forename: Ralf
authors.initials: R
authors.lastname: Pasternack
authors.forename: Martin
authors.initials: M
authors.lastname: Hils
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity; D010455:Peptides / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D011422:Propionates / Q000633:toxicity; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D006657:Histones; D009574:Nitro Compounds; C486497:PPARGC1A protein, human; D010455:Peptides; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011422:Propionates; D014157:Transcription Factors; D045304:Cytochromes c; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; C015392:3-nitropropionic acid