Human Molecular Genetics Advance Access published online on July 17, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn211
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Compensatory changes in the ubiquitin-proteasome system, BDNF and mitochondrial complex II / III in YAC72 and R6/2 transgenic mice partially model Huntington's disease (HD) patients
1 Department of Molecular and Life Sciences, Hanyang University, Gyeonggi-do 426-791, South Korea 2 Neuroregeneration Laboratories, Center for Neuroregeneration Research, McLean Hospital and Harvard Medical School, Belmont, MA 02478
* Correspondence: Dr. Ole Isacson, Neuroregeneration Laboratories, Center for Neuroregeneration Research, McLean Hospital/Harvard Medical School, 115 Mill St., Belmont, MA 02478, isacson{at}hms.harvard.edu, hseo{at}hanyang.ac.kr
Received April 2, 2008; Revised July 16, 2008; Accepted July 16, 2008
Intraneuronal protein aggregates of the mutated huntingtin in Huntington's disease (HD) brains suggest an over-load 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) at 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 at 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 BDNF expression 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 mitochondrial complex II/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.
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