Open AccessInhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease
Author(s) -
McConoughey Stephen J.,
Basso Manuela,
Niatsetskaya Zoya V.,
Sleiman Sama F.,
Smirnova Natalia A.,
Langley Brett C.,
Mahishi Lata,
Cooper Arthur J. L.,
Antonyak Marc A.,
Cerione Rick A.,
Li Bo,
Starkov Anatoly,
Chaturvedi Rajnish Kumar,
Beal M. Flint,
Coppola Giovanni,
Geschwind Daniel H.,
Ryu Hoon,
Xia Li,
Iismaa Siiri E.,
Pallos Judit,
Pasternack Ralf,
Hils Martin,
Fan Jing,
Raymond Lynn A.,
Marsh J. Lawrence,
Thompson Leslie M.,
Ratan Rajiv R.
Publication year - 2010
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201000084
Subject(s) - tissue transglutaminase , huntington's disease , immune dysregulation , disease , hek 293 cells , microbiology and biotechnology , chemistry , neuroscience , biology , medicine , genetics , enzyme , gene , biochemistry
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‐1α 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.