. Progressive loss of BDNF in a mouse model of Huntington's disease and rescue by BDNF delivery. Pharmacol Res. 2005 Aug;52(2):133-9. PubMed.


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  1. Elena Cattaneo’s beautiful paper in Science (Zuccato et al., 2001) demonstrated clearly that in transfected cells and in transgenic animals, wild-type and mutant huntingtin modulate BDNF transcription in opposite directions. In conditionally immortalized rat embryonic striatal neurons transfected with wild-type or mutant huntingtin, wild-type huntingtin increased BDNF by upregulating transcription from exon 2, whereas mutant huntingtin decreased BDNF by downregulating transcripts 2, 3 and 4. In transgenic mice overexpressing wild-type huntingtin, exons 2 and 3 mRNA levels in cerebral cortex and hippocampus were higher than in wild-type littermates. In the same tissues from mice overexpressing mutant huntingtin, exons 2, 3 and 4 mRNAs were decreased. The age of the mice under study was not indicated.

    In this new paper by the same group, the transgenic mouse data from the Science paper is expanded to provide a time course. Although the transgenic mouse strain is different (YAC18 and YAC72 mice in the Science paper, R6/2 mice here), there are no surprises. In the HD mice, BDNF exon 2 decreases significantly after 8 weeks, exon 3 after 12 weeks, and exon 4 after 6 weeks. The mice first exhibit symptoms at 6 weeks of age. Therefore, it is not entirely clear from this study that the decrease in BDNF occurs sufficiently early or is large enough (the proportion of BDNF protein derived from exon 4 is unknown) to be responsible for the neurological dysfunction in these mice.

    BDNF mRNA and protein levels are lower in human HD cerebral cortex than in controls, as reported by this group in their Science paper. Decreased BDNF protein in human cerebral cortex of HD subjects is controversial, however. Therefore, although the data from cell culture and transgenic mouse models of HD is convincing, more data from human subjects is needed. In particular, the human BDNF gene is somewhat more complicated than the rat gene, with seven upstream exons instead of four. BDNF exon 1 is expressed in human cerebral cortex, in contrast to the rodent. Since exon 1 transcripts are downregulated in Alzheimer disease (Garzon et al., 2002), it will be interesting to determine whether the rodent models of HD accurately predict the changes in BDNF mRNA in the human HD brain.


    . Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science. 2001 Jul 20;293(5529):493-8. PubMed.

    . A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer's disease parietal cortex. J Neurochem. 2002 Sep;82(5):1058-64. PubMed.

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