Overexpression and nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase in a transgenic mouse model of Huntington's disease.
Huntington's disease is due to an expansion of CAG repeats in the huntingtin gene. Huntingtin interacts with several proteins including glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We performed immunohistochemical analysis of GAPDH expression in the brains of transgenic mice carrying the huntingtin gene with 89 CAG repeats. In all wild-type animals examined, GAPDH was evenly distributed among the different cell types throughout the brain. In contrast, the majority of transgenic mice showed GAPDH overexpression, with the most prominent GAPDH changes observed in the caudate putamen, globus pallidus, neocortex, and hippocampal formation. Double staining for NeuN and GFAP revealed that GAPDH overexpression occurred exclusively in neurons. Nissl staining analysis of the neocortex and caudate putamen indicated 24 and 27% of cell loss in transgenic mice, respectively. Subcellular fluorescence analysis revealed a predominant increase in GAPDH immunostaining in the nucleus. Thus, we conclude that mutation of huntingtin is associated with GAPDH overexpression and nuclear translocation in discrete populations of brain neurons.
Senatorov
Vladimir V
VV
Molecular Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, MD 20892-1363, Bethesda, USA.
Charles
Vinod
V
Reddy
P H
PH
Tagle
Dan A
DA
Chuang
De-Maw
DM
D000818:Animals; D002421:Caudate Nucleus / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics* / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000201:enzymology / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019680:Trinucleotide Repeat Expansion
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)