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.
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.
Seo
Hyemyung
H
Neuroregeneration Laboratories, Center for Neuroregeneration Research, McLean Hospital, Harvard MedicalSchool, 115 Mill Street, Belmont, MA 02478, USA.
Kim
Woori
W
Isacson
Ole
O
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D042963:Electron Transport Complex II / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D025801:Ubiquitin; D042963:Electron Transport Complex II; D046988:Proteasome Endopeptidase Complex; D014450:Electron Transport Complex III