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

Jill R. Crittenden, Denise E. Dunn, Farhan I. 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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Crittenden, J. R., Dunn, D. E., Merali, F. I., Woodman, B., Yim, M., Borkowska, A. E., Frosch, M. P., Bates, G. P., Housman, D. E., Lo, D. C., & 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