Caldag-Gefi Down-Regulation in the Striatum as a Neuroprotective Change in Huntington's Disease.
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Crittenden_et_al_2010_Human_Molecular_Genetics.pdf
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Author(s)
Dunn, Denise E.
Merali, Farhan I.
Woodman, Ben
Yim, Michael
Borkowska, Anna E.
Frosch, Matthew P.
Bates, Gillian P.
Lo, Donald C.
Crittenden, Jill R
Housman, David E
Date Issued
February 2010
Journal
Human Molecular Genetics
Publisher
IRL Press at Oxford University Press
Citation
Crittenden, Jill R. "CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease." Human Molecular Genetics 19.9 (2010): 1756-65.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1093/hmg/ddq055
