Mutant huntingtin protein: A substrate for transglutaminase 1, 2, and 3

Gina M. Zainelli, Nichole L. Dudek, Christopher A Ross, Soo Youl Kim, Nancy A. Muma

Research output: Contribution to journalArticle

Abstract

The most prominent neuropathologic hallmarks of Huntington disease (HD) are cortical and striatal perinuclear cytoplasmic aggregates and intranuclear inclusions of mutant huntingtin. Our laboratory previously demonstrated that huntingtin protein colocalizes with transglutaminase 2 and its product, the ε-(γ-glutamyl)lysine bond in intranuclear inclusions in HD frontal cortex. We also found that transglutaminase 2 cross-links N-terminal fragments of mutant huntingtin (htt-N63-148Q-myc) in cells in culture. We now report a significant increase in transglutaminase 2 mRNA in HD cortex (225% of controls) and striatum (399% of controls). Expression of the short transglutaminase 2 mRNA splice variant was not detectable in HD, although previous studies demonstrated upregulation in Alzheimer disease and progressive supranuclear palsy. Cells co-transfected with GFP-tagged transglutaminase 1, 2, or 3 and htt-N63-148Q-myc exhibit increased cross-linked huntingtin in the insoluble fraction of cell lysates. Treatment of cells with cystamine, a chemical inhibitor of transglutaminase, decreased aggregated and cross-linked huntingtin and increased viability of cells that were transfected with transglutaminase 2 and htt-N63-148Q-myc. These data suggest that transglutaminase 1, 2, and 3 could be involved in cross-linking of huntingtin into intranuclear inclusions in HD and that inhibiting transglutaminase should be explored as a potential treatment strategy for HD.

Original languageEnglish (US)
Pages (from-to)58-65
Number of pages8
JournalJournal of Neuropathology and Experimental Neurology
Volume64
Issue number1
StatePublished - Jan 2005

Fingerprint

Staphylococcal Protein A
Mutant Proteins
Huntington Disease
Intranuclear Inclusion Bodies
Transglutaminases
Cystamine
Progressive Supranuclear Palsy
Corpus Striatum
Messenger RNA
Inclusion Bodies
Frontal Lobe
Huntingtin Protein
transglutaminase 1
transglutaminase 2
Lysine
Cell Survival
Alzheimer Disease
Up-Regulation
Cell Culture Techniques

Keywords

  • Aggregation
  • Cell death
  • Cross-linking
  • Huntingtin
  • Huntington disease
  • Transglutaminase

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

Mutant huntingtin protein : A substrate for transglutaminase 1, 2, and 3. / Zainelli, Gina M.; Dudek, Nichole L.; Ross, Christopher A; Kim, Soo Youl; Muma, Nancy A.

In: Journal of Neuropathology and Experimental Neurology, Vol. 64, No. 1, 01.2005, p. 58-65.

Research output: Contribution to journalArticle

Zainelli, Gina M. ; Dudek, Nichole L. ; Ross, Christopher A ; Kim, Soo Youl ; Muma, Nancy A. / Mutant huntingtin protein : A substrate for transglutaminase 1, 2, and 3. In: Journal of Neuropathology and Experimental Neurology. 2005 ; Vol. 64, No. 1. pp. 58-65.
@article{6da07f7a2d6e4c879c6daf69b68947e3,
title = "Mutant huntingtin protein: A substrate for transglutaminase 1, 2, and 3",
abstract = "The most prominent neuropathologic hallmarks of Huntington disease (HD) are cortical and striatal perinuclear cytoplasmic aggregates and intranuclear inclusions of mutant huntingtin. Our laboratory previously demonstrated that huntingtin protein colocalizes with transglutaminase 2 and its product, the ε-(γ-glutamyl)lysine bond in intranuclear inclusions in HD frontal cortex. We also found that transglutaminase 2 cross-links N-terminal fragments of mutant huntingtin (htt-N63-148Q-myc) in cells in culture. We now report a significant increase in transglutaminase 2 mRNA in HD cortex (225{\%} of controls) and striatum (399{\%} of controls). Expression of the short transglutaminase 2 mRNA splice variant was not detectable in HD, although previous studies demonstrated upregulation in Alzheimer disease and progressive supranuclear palsy. Cells co-transfected with GFP-tagged transglutaminase 1, 2, or 3 and htt-N63-148Q-myc exhibit increased cross-linked huntingtin in the insoluble fraction of cell lysates. Treatment of cells with cystamine, a chemical inhibitor of transglutaminase, decreased aggregated and cross-linked huntingtin and increased viability of cells that were transfected with transglutaminase 2 and htt-N63-148Q-myc. These data suggest that transglutaminase 1, 2, and 3 could be involved in cross-linking of huntingtin into intranuclear inclusions in HD and that inhibiting transglutaminase should be explored as a potential treatment strategy for HD.",
keywords = "Aggregation, Cell death, Cross-linking, Huntingtin, Huntington disease, Transglutaminase",
author = "Zainelli, {Gina M.} and Dudek, {Nichole L.} and Ross, {Christopher A} and Kim, {Soo Youl} and Muma, {Nancy A.}",
year = "2005",
month = "1",
language = "English (US)",
volume = "64",
pages = "58--65",
journal = "American Journal of Psychotherapy",
issn = "0002-9564",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Mutant huntingtin protein

T2 - A substrate for transglutaminase 1, 2, and 3

AU - Zainelli, Gina M.

AU - Dudek, Nichole L.

AU - Ross, Christopher A

AU - Kim, Soo Youl

AU - Muma, Nancy A.

PY - 2005/1

Y1 - 2005/1

N2 - The most prominent neuropathologic hallmarks of Huntington disease (HD) are cortical and striatal perinuclear cytoplasmic aggregates and intranuclear inclusions of mutant huntingtin. Our laboratory previously demonstrated that huntingtin protein colocalizes with transglutaminase 2 and its product, the ε-(γ-glutamyl)lysine bond in intranuclear inclusions in HD frontal cortex. We also found that transglutaminase 2 cross-links N-terminal fragments of mutant huntingtin (htt-N63-148Q-myc) in cells in culture. We now report a significant increase in transglutaminase 2 mRNA in HD cortex (225% of controls) and striatum (399% of controls). Expression of the short transglutaminase 2 mRNA splice variant was not detectable in HD, although previous studies demonstrated upregulation in Alzheimer disease and progressive supranuclear palsy. Cells co-transfected with GFP-tagged transglutaminase 1, 2, or 3 and htt-N63-148Q-myc exhibit increased cross-linked huntingtin in the insoluble fraction of cell lysates. Treatment of cells with cystamine, a chemical inhibitor of transglutaminase, decreased aggregated and cross-linked huntingtin and increased viability of cells that were transfected with transglutaminase 2 and htt-N63-148Q-myc. These data suggest that transglutaminase 1, 2, and 3 could be involved in cross-linking of huntingtin into intranuclear inclusions in HD and that inhibiting transglutaminase should be explored as a potential treatment strategy for HD.

AB - The most prominent neuropathologic hallmarks of Huntington disease (HD) are cortical and striatal perinuclear cytoplasmic aggregates and intranuclear inclusions of mutant huntingtin. Our laboratory previously demonstrated that huntingtin protein colocalizes with transglutaminase 2 and its product, the ε-(γ-glutamyl)lysine bond in intranuclear inclusions in HD frontal cortex. We also found that transglutaminase 2 cross-links N-terminal fragments of mutant huntingtin (htt-N63-148Q-myc) in cells in culture. We now report a significant increase in transglutaminase 2 mRNA in HD cortex (225% of controls) and striatum (399% of controls). Expression of the short transglutaminase 2 mRNA splice variant was not detectable in HD, although previous studies demonstrated upregulation in Alzheimer disease and progressive supranuclear palsy. Cells co-transfected with GFP-tagged transglutaminase 1, 2, or 3 and htt-N63-148Q-myc exhibit increased cross-linked huntingtin in the insoluble fraction of cell lysates. Treatment of cells with cystamine, a chemical inhibitor of transglutaminase, decreased aggregated and cross-linked huntingtin and increased viability of cells that were transfected with transglutaminase 2 and htt-N63-148Q-myc. These data suggest that transglutaminase 1, 2, and 3 could be involved in cross-linking of huntingtin into intranuclear inclusions in HD and that inhibiting transglutaminase should be explored as a potential treatment strategy for HD.

KW - Aggregation

KW - Cell death

KW - Cross-linking

KW - Huntingtin

KW - Huntington disease

KW - Transglutaminase

UR - http://www.scopus.com/inward/record.url?scp=13244253858&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13244253858&partnerID=8YFLogxK

M3 - Article

C2 - 15715085

AN - SCOPUS:13244253858

VL - 64

SP - 58

EP - 65

JO - American Journal of Psychotherapy

JF - American Journal of Psychotherapy

SN - 0002-9564

IS - 1

ER -