PMID- 18640989
OWN - NLM
STAT- MEDLINE
DCOM- 20081112
LR  - 20211020
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 17
IP  - 20
DP  - 2008 Oct 15
TI  - Compensatory changes in the ubiquitin-proteasome system, brain-derived 
      neurotrophic factor and mitochondrial complex II/III in YAC72 and R6/2 transgenic 
      mice partially model Huntington's disease patients.
PG  - 3144-53
LID - 10.1093/hmg/ddn211 [doi]
AB  - Intraneuronal protein aggregates of the mutated huntingtin in Huntington's 
      disease (HD) brains suggest an overload and/or dysfunction of the 
      ubiquitin-proteasome system (UPS). There is a general inhibition of the UPS in 
      many brain regions (cerebellum, cortex, substantia nigra and caudate-putamen) and 
      skin fibroblasts from HD patients. In the current experiment, the widely used 
      mutant huntingtin-exon 1 CAG repeat HD transgenic mice model (R6/2) (with 144 CAG 
      repeat and exon 1) during late-stage pathology, had increases in proteasome 
      activity in the striatum. However, this discrepancy with HD patient tissue was 
      not apparent in the mutant CAG repeat huntingtin full-length HD (YAC72) 
      transgenic mouse model during post-symptomatic and late-stage pathology, which 
      then also showed UPS inhibition similar to HD patients' brains. In both types of 
      HD model mice, we determined biochemical changes, including expression of 
      brain-derived neurotrophic factor (BDNF) and mitochondrial complex II/III 
      (MCII/III) activities related to HD pathology. We found increases of both BDNF 
      expression, and MCII/III activities in YAC72 transgenic mice, and no change of 
      BDNF expression in R6/2 mice. Our data show that extreme CAG repeat lengths in 
      R6/2 mice is paradoxically associated with increased proteasome activity, 
      probably as a cellular compensatory biochemical change in response to the 
      underlying mutation. Changes in HD patients for UPS function, BDNF expression and 
      MCII/III activity are only partially modeled in R6/2 and YAC72 mice, with the 
      latter at 16 months of age being most congruent with the human disease.
FAU - Seo, Hyemyung
AU  - Seo H
AD  - Neuroregeneration Laboratories, Center for Neuroregeneration Research, McLean 
      Hospital, Harvard MedicalSchool, 115 Mill Street, Belmont, MA 02478, USA.
FAU - Kim, Woori
AU  - Kim W
FAU - Isacson, Ole
AU  - Isacson O
LA  - eng
GR  - NS-30064/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080717
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (HTT protein, human)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Ubiquitin)
RN  - EC 1.3.5.1 (Electron Transport Complex II)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - EC 7.1.1.8 (Electron Transport Complex III)
SB  - IM
MH  - Animals
MH  - Behavior, Animal
MH  - Brain/metabolism/pathology
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Disease Models, Animal
MH  - Electron Transport Complex II/*metabolism
MH  - Electron Transport Complex III/*metabolism
MH  - Humans
MH  - Huntingtin Protein
MH  - Huntington Disease/*genetics/*metabolism/pathology/psychology
MH  - Mice
MH  - Mice, Transgenic
MH  - Models, Neurological
MH  - Nerve Tissue Proteins/genetics
MH  - Nuclear Proteins/genetics
MH  - Proteasome Endopeptidase Complex/*metabolism
MH  - Recombinant Proteins/genetics
MH  - Ubiquitin/*metabolism
PMC - PMC2556853
EDAT- 2008/07/22 09:00
MHDA- 2008/11/13 09:00
PMCR- 2009/10/15
CRDT- 2008/07/22 09:00
PHST- 2008/07/22 09:00 [pubmed]
PHST- 2008/11/13 09:00 [medline]
PHST- 2008/07/22 09:00 [entrez]
PHST- 2009/10/15 00:00 [pmc-release]
AID - ddn211 [pii]
AID - 10.1093/hmg/ddn211 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2008 Oct 15;17(20):3144-53. doi: 10.1093/hmg/ddn211. Epub 2008 Jul 
      17.