Journal Article

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 and Ann M. Graybiel

in Human Molecular Genetics

Volume 19, issue 9, pages 1756-1765
Published in print May 2010 | ISSN: 0964-6906
Published online February 2010 | e-ISSN: 1460-2083 | DOI:
CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease

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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.

Journal Article.  6547 words.  Illustrated.

Subjects: Genetics and Genomics

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