Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease.
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.
McConoughey
Stephen J
SJ
Burke Medical Research Institute, White Plains, NY, USA.
Basso
Manuela
M
Niatsetskaya
Zoya V
ZV
Sleiman
Sama F
SF
Smirnova
Natalia A
NA
Langley
Brett C
BC
Mahishi
Lata
L
Cooper
Arthur J L
AJ
Antonyak
Marc A
MA
Cerione
Rick A
RA
Li
Bo
B
Starkov
Anatoly
A
Chaturvedi
Rajnish Kumar
RK
Beal
M Flint
MF
Coppola
Giovanni
G
Geschwind
Daniel H
DH
Ryu
Hoon
H
Xia
Li
L
Iismaa
Siiri E
SE
Pallos
Judit
J
Pasternack
Ralf
R
Hils
Martin
M
Fan
Jing
J
Raymond
Lynn A
LA
Marsh
J Lawrence
JL
Thompson
Leslie M
LM
Ratan
Rajiv R
RR
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
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