CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease

Jill R. Crittenden, Denise E. Dunn, Farhan Merali, Ben Woodman, Michael Yim, Anna E. Borkowska, Matthew P. Frosch, Gillian P. Bates, David E. Housman, Donald C. Lo, Ann M. Graybiel

Research output: Contribution to journalArticle

Abstract

Huntingtin protein (Htt) is ubiquitously expressed, yet Huntington's disease (HD), a fatal neurologic disorder produced by expansion of an Htt polyglutamine tract, is characterized by neurodegeneration that occurs primarily in the striatum and cerebral cortex. Such discrepancies between sites of expression and pathology occur in multiple neurodegenerative disorders associated with expanded polyglutamine tracts. One possible reason is that disease-modifying factors are tissue-specific. Here, we show that the striatum-enriched protein, CalDAG-GEFI, is severely down-regulated in the striatum of mouse HD models and is down-regulated in HD individuals. In the R6/2 transgenic mouse model of HD, striatal neurons with the largest aggregates of mutant Htt have the lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. These findings suggest that the striking down-regulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates Htt-induced degeneration.

Original languageEnglish (US)
Article numberddq055
Pages (from-to)1756-1765
Number of pages10
JournalHuman Molecular Genetics
Volume19
Issue number9
DOIs
StatePublished - Feb 10 2010
Externally publishedYes

Fingerprint

Huntington Disease
Down-Regulation
Corpus Striatum
Pathology
Neurons
Thromboplastin
Mutant Proteins
Nervous System Diseases
Neurodegenerative Diseases
Cerebral Cortex
Transgenic Mice
Transfection
Exons
Huntingtin Protein
Brain
polyglutamine
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Crittenden, J. R., Dunn, D. E., Merali, F., Woodman, B., Yim, M., Borkowska, A. E., ... Graybiel, A. M. (2010). CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease. Human Molecular Genetics, 19(9), 1756-1765. [ddq055]. https://doi.org/10.1093/hmg/ddq055

CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease. / Crittenden, Jill R.; Dunn, Denise E.; Merali, Farhan; Woodman, Ben; Yim, Michael; Borkowska, Anna E.; Frosch, Matthew P.; Bates, Gillian P.; Housman, David E.; Lo, Donald C.; Graybiel, Ann M.

In: Human Molecular Genetics, Vol. 19, No. 9, ddq055, 10.02.2010, p. 1756-1765.

Research output: Contribution to journalArticle

Crittenden, JR, Dunn, DE, Merali, F, Woodman, B, Yim, M, Borkowska, AE, Frosch, MP, Bates, GP, Housman, DE, Lo, DC & Graybiel, AM 2010, 'CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease', Human Molecular Genetics, vol. 19, no. 9, ddq055, pp. 1756-1765. https://doi.org/10.1093/hmg/ddq055
Crittenden JR, Dunn DE, Merali F, Woodman B, Yim M, Borkowska AE et al. CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease. Human Molecular Genetics. 2010 Feb 10;19(9):1756-1765. ddq055. https://doi.org/10.1093/hmg/ddq055
Crittenden, Jill R. ; Dunn, Denise E. ; Merali, Farhan ; Woodman, Ben ; Yim, Michael ; Borkowska, Anna E. ; Frosch, Matthew P. ; Bates, Gillian P. ; Housman, David E. ; Lo, Donald C. ; Graybiel, Ann M. / CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 9. pp. 1756-1765.
@article{cacdcfd96beb4212b84857dfe710f597,
title = "CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease",
abstract = "Huntingtin protein (Htt) is ubiquitously expressed, yet Huntington's disease (HD), a fatal neurologic disorder produced by expansion of an Htt polyglutamine tract, is characterized by neurodegeneration that occurs primarily in the striatum and cerebral cortex. Such discrepancies between sites of expression and pathology occur in multiple neurodegenerative disorders associated with expanded polyglutamine tracts. One possible reason is that disease-modifying factors are tissue-specific. Here, we show that the striatum-enriched protein, CalDAG-GEFI, is severely down-regulated in the striatum of mouse HD models and is down-regulated in HD individuals. In the R6/2 transgenic mouse model of HD, striatal neurons with the largest aggregates of mutant Htt have the lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. These findings suggest that the striking down-regulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates Htt-induced degeneration.",
author = "Crittenden, {Jill R.} and Dunn, {Denise E.} and Farhan Merali and Ben Woodman and Michael Yim and Borkowska, {Anna E.} and Frosch, {Matthew P.} and Bates, {Gillian P.} and Housman, {David E.} and Lo, {Donald C.} and Graybiel, {Ann M.}",
year = "2010",
month = "2",
day = "10",
doi = "10.1093/hmg/ddq055",
language = "English (US)",
volume = "19",
pages = "1756--1765",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "9",

}

TY - JOUR

T1 - CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease

AU - Crittenden, Jill R.

AU - Dunn, Denise E.

AU - Merali, Farhan

AU - Woodman, Ben

AU - Yim, Michael

AU - Borkowska, Anna E.

AU - Frosch, Matthew P.

AU - Bates, Gillian P.

AU - Housman, David E.

AU - Lo, Donald C.

AU - Graybiel, Ann M.

PY - 2010/2/10

Y1 - 2010/2/10

N2 - Huntingtin protein (Htt) is ubiquitously expressed, yet Huntington's disease (HD), a fatal neurologic disorder produced by expansion of an Htt polyglutamine tract, is characterized by neurodegeneration that occurs primarily in the striatum and cerebral cortex. Such discrepancies between sites of expression and pathology occur in multiple neurodegenerative disorders associated with expanded polyglutamine tracts. One possible reason is that disease-modifying factors are tissue-specific. Here, we show that the striatum-enriched protein, CalDAG-GEFI, is severely down-regulated in the striatum of mouse HD models and is down-regulated in HD individuals. In the R6/2 transgenic mouse model of HD, striatal neurons with the largest aggregates of mutant Htt have the lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. These findings suggest that the striking down-regulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates Htt-induced degeneration.

AB - Huntingtin protein (Htt) is ubiquitously expressed, yet Huntington's disease (HD), a fatal neurologic disorder produced by expansion of an Htt polyglutamine tract, is characterized by neurodegeneration that occurs primarily in the striatum and cerebral cortex. Such discrepancies between sites of expression and pathology occur in multiple neurodegenerative disorders associated with expanded polyglutamine tracts. One possible reason is that disease-modifying factors are tissue-specific. Here, we show that the striatum-enriched protein, CalDAG-GEFI, is severely down-regulated in the striatum of mouse HD models and is down-regulated in HD individuals. In the R6/2 transgenic mouse model of HD, striatal neurons with the largest aggregates of mutant Htt have the lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. These findings suggest that the striking down-regulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates Htt-induced degeneration.

UR - http://www.scopus.com/inward/record.url?scp=77952504137&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952504137&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddq055

DO - 10.1093/hmg/ddq055

M3 - Article

C2 - 20147317

AN - SCOPUS:77952504137

VL - 19

SP - 1756

EP - 1765

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 9

M1 - ddq055

ER -