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: Stephen J McConoughey, Manuela Basso, Zoya V Niatsetskaya, Sama F Sleiman, Natalia A Smirnova, Brett C Langley, Lata Mahishi, Arthur J L Cooper, Marc A Antonyak, Rick A Cerione, Bo Li, Anatoly Starkov, Rajnish Kumar Chaturvedi, M Flint Beal, Giovanni Coppola, Daniel H Geschwind, Hoon Ryu, Li Xia, Siiri E Iismaa, Judit Pallos, Ralf Pasternack, Martin Hils, Jing Fan, Lynn A Raymond, J Lawrence Marsh, Leslie M Thompson, Rajiv R Ratan
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 2 Issue 9 Pg. 349-70 (Sep 2010) ISSN: 1757-4684 [Electronic] England
• PMID: 20665636 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Heat-Shock Proteins
• Histones
• Nitro Compounds
• PPARGC1A protein, human
• Peptides
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Propionates
• Transcription Factors
• Cytochromes c
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• GTP-Binding Proteins
• 3-nitropropionic acid

Topics

• Amino Acid Sequence
• Animals
• Cell Line, Tumor
• Cytochromes c (genetics, metabolism)
• Disease Models, Animal
• Drosophila
• Energy Metabolism
• Enzyme Inhibitors (pharmacology)
• GTP-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• Heat-Shock Proteins (genetics, metabolism)
• Histones (metabolism)
• Humans
• Huntington Disease (enzymology, genetics, metabolism)
• Mice
• Mitochondria (metabolism)
• Nitro Compounds (toxicity)
• Peptides (pharmacology)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Promoter Regions, Genetic
• Propionates (toxicity)
• Protein Glutamine gamma Glutamyltransferase 2
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• Transglutaminases (antagonists & inhibitors, genetics, metabolism)