Journal Article

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

Hyemyung Seo, Woori Kim and Ole Isacson

in Human Molecular Genetics

Volume 17, issue 20, pages 3144-3153
Published in print October 2008 | ISSN: 0964-6906
Published online July 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn211
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

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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.

Journal Article.  4935 words.  Illustrated.

Subjects: Genetics and Genomics

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