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

Abstract

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.

Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease

“…At late stage of disease (12 months), we found that both striatal and cortical mBDNF levels are markedly reduced, which correlate with overt onset of behavioral and cognitive symptoms. The age- and region-dependent reduction of mBDNF is consistent with progressive loss of bdnf gene transcription (Gines et al, 2003; Zuccato et al, 2005; Seo et al, 2008; Bobrowska et al, 2011; Sontag et al, 2012; Plotkin et al, 2014). …”

“…Although reduced trophic support of BDNF has been proposed as an underlying mechanism in HD pathogenesis, prior studies in HD mouse models showed conflicting results regarding the levels of BDNF in the cortex and the striatum (Gines et al, 2003; Seo et al, 2008; Bobrowska et al, 2011; Sontag et al, 2012; Plotkin et al, 2014). Moreover, the ratio of proBDNF to mBDNF in the striatum of wild type and HD mice remains unknown.…”

“…Deficiency in BDNF trophic support has been proposed as an important mechanism underlying HD pathogenesis. However, prior studies have reported inconsistent results regarding levels of BDNF and its receptors in different HD mouse models (Gines et al, 2003; Zuccato et al, 2005; Seo et al, 2008; Bobrowska et al, 2011; Sontag et al, 2012; Plotkin et al, 2014). Furthermore, given that proBDNF and mBDNF have opposing effects on cell survival, the question of whether BDNF maturation is impaired in HD needs to be determined.…”

BDNF Overexpression in the Forebrain Rescues Huntington's Disease Phenotypes in YAC128 Mice

“…In this study, we found that striatal levels of mature BDNF were also reduced in YAC128 mice. However, ELISA assays show normal striatal levels of BDNF in R6/1 mice (Canals et al, 2004; Pang et al, 2006) and increased striatal levels of BDNF in YAC72 mice (Seo et al, 2008). As ELISA assays detect both mature BDNF and proBDNF, this discrepancy suggests that processing of proBDNF may be impaired in the striatum, leading to accumulation of proBDNF in the striatum.…”

Acute Polyglutamine Expression in Inducible Mouse Model Unravels Ubiquitin/Proteasome System Impairment and Permanent Recovery Attributable to Aggregate Formation

“…Similar to the Western blot data, proteasome activity assays on striatal homogenates showed a trend of decreased caspase-like activity only after 1 week of transgene expression (15.6 Ϯ 18.8% decrease, p ϭ 0.54). In the case of chymotrypsin activity, the opposite result (a trend of increased activity) was observed (data not shown), which can be easily explained by the fact that a selective upregulation of this activity is well established in N-mutHtt mouse models (Diaz-Hernandez et al, 2003;Seo et al, 2004;Bett et al, 2006;Seo et al, 2008). …”