PMID- 17959817
OWN - NLM
STAT- MEDLINE
DCOM- 20071108
LR  - 20211020
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 27
IP  - 43
DP  - 2007 Oct 24
TI  - Expression profiling of Huntington's disease models suggests that brain-derived 
      neurotrophic factor depletion plays a major role in striatal degeneration.
PG  - 11758-68
AB  - Many pathways have been proposed as contributing to Huntington's disease (HD) 
      pathogenesis, but generally the in vivo effects of their perturbation have not 
      been compared with reference data from human patients. Here we examine how 
      accurately mechanistically motivated and genetic HD models recapitulate the 
      striatal gene expression phenotype of human HD. The representative genetic model 
      was the R6/2 transgenic mouse, which expresses a fragment of the huntingtin 
      protein containing a long CAG repeat. Pathogenic mechanisms examined include 
      mitochondrial dysfunction; profiled in 3-nitropropionic acid-treated rats, 
      1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, and PGC-1alpha 
      knock-out mice; and depletion of brain-derived neurotrophic factor (BDNF) using 
      heterozygous and forebrain-specific BDNF-knock-out mice (BDNF(HET), 
      Emx-BDNF(KO)). Based on striatal gene expression, we find the BDNF models, both 
      heterozygous and homozygous knock-outs, to be more like human HD than the other 
      HD models. This implicates reduced trophic support as a major pathway 
      contributing to striatal degeneration in HD. Because the majority of striatal 
      BDNF is synthesized by cortical neurons, the data also imply that cortical 
      dysfunction contributes to HD's hallmark effects on the basal ganglia. Finally, 
      the results suggest that striatal lesions caused by mitochondrial toxins may 
      arise via pathways different from those that drive neurodegeneration in HD. Based 
      on these findings, we present a testable model of HD pathogenesis that, unlike 
      most models, begins to account for regional specificity in human HD and the 
      absence of such specificity in genetic mouse models of HD.
FAU - Strand, Andrew D
AU  - Strand AD
AD  - Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. 
      astrand@fhcrc.org
FAU - Baquet, Zachary C
AU  - Baquet ZC
FAU - Aragaki, Aaron K
AU  - Aragaki AK
FAU - Holmans, Peter
AU  - Holmans P
FAU - Yang, Lichuan
AU  - Yang L
FAU - Cleren, Carine
AU  - Cleren C
FAU - Beal, M Flint
AU  - Beal MF
FAU - Jones, Lesley
AU  - Jones L
FAU - Kooperberg, Charles
AU  - Kooperberg C
FAU - Olson, James M
AU  - Olson JM
FAU - Jones, Kevin R
AU  - Jones KR
LA  - eng
GR  - R01 CA74841/CA/NCI NIH HHS/United States
GR  - R01 EY014998/EY/NEI NIH HHS/United States
GR  - R01 NS042157-04/NS/NINDS NIH HHS/United States
GR  - R21 NS0475098-01A1/NS/NINDS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Brain-Derived Neurotrophic Factor)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*deficiency/genetics
MH  - Corpus Striatum/*metabolism/pathology
MH  - *Disease Models, Animal
MH  - Gene Expression Profiling/*methods
MH  - Humans
MH  - Huntington Disease/genetics/*metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Nerve Degeneration/genetics/*metabolism/pathology
MH  - Rats
MH  - Rats, Inbred Lew
PMC - PMC6673215
EDAT- 2007/10/26 09:00
MHDA- 2007/11/09 09:00
PMCR- 2008/04/24
CRDT- 2007/10/26 09:00
PHST- 2007/10/26 09:00 [pubmed]
PHST- 2007/11/09 09:00 [medline]
PHST- 2007/10/26 09:00 [entrez]
PHST- 2008/04/24 00:00 [pmc-release]
AID - 27/43/11758 [pii]
AID - 3279666 [pii]
AID - 10.1523/JNEUROSCI.2461-07.2007 [doi]
PST - ppublish
SO  - J Neurosci. 2007 Oct 24;27(43):11758-68. doi: 10.1523/JNEUROSCI.2461-07.2007.