1 research outputs found
Caldag-Gefi Down-Regulation in the Striatum as a Neuroprotective Change in Huntington's Disease.
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.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (R01-HD28341)National Institute of Mental Health (U.S.) (F32-MH065815)Wellcome Trust (London, England)Cure Huntington’s Disease Initiative, Inc.MGH/MIT Morris Udall Center of Excellence in Parkinson Disease Research (P50-NS038372