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.
Crittenden
Jill R
JR
McGovern Institute for Brain Research, MIT, 43 Vassar Street, Building 46-6133, Cambridge, MA, USA.
Dunn
Denise E
DE
Merali
Farhan I
FI
Woodman
Ben
B
Yim
Michael
M
Borkowska
Anna E
AE
Frosch
Matthew P
MP
Bates
Gillian P
GP
Housman
David E
DE
Lo
Donald C
DC
Graybiel
Ann M
AM
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D020662:Guanine Nucleotide Exchange Factors; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C485927:Rasgrp2 protein, mouse