Caldag-Gefi Down-Regulation in the Striatum as a Neuroprotective Change in Huntington's Disease.
Author(s)Crittenden, Jill R.; Dunn, Denise E.; Merali, Farhan I.; Woodman, Ben; Yim, Michael; Borkowska, Anna E.; Frosch, Matthew P.; Bates, Gillian P.; Housman, David E.; Lo, Donald C.; Graybiel, Ann M.; ... Show more Show less
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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.
Departmentmove to dc.description.sponsorship; move to dc.description.sponsorship; David H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences; McGovern Institute for Brain Research at MIT
Human Molecular Genetics
IRL Press at Oxford University Press
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.
Author's final manuscript