Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab

Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA.
Cell Metabolism (Impact Factor: 17.57). 12/2006; 4(5):349-62. DOI: 10.1016/j.cmet.2006.10.004
Source: PubMed


Huntington's disease (HD) is a fatal, dominantly inherited disorder caused by polyglutamine repeat expansion in the huntingtin (htt) gene. Here, we observe that HD mice develop hypothermia associated with impaired activation of brown adipose tissue (BAT). Although sympathetic stimulation of PPARgamma coactivator 1alpha (PGC-1alpha) was intact in BAT of HD mice, uncoupling protein 1 (UCP-1) induction was blunted. In cultured cells, expression of mutant htt suppressed UCP-1 promoter activity; this was reversed by PGC-1alpha expression. HD mice showed reduced food intake and increased energy expenditure, with dysfunctional BAT mitochondria. PGC-1alpha is a known regulator of mitochondrial function; here, we document reduced expression of PGC-1alpha target genes in HD patient and mouse striatum. Mitochondria of HD mouse brain show reduced oxygen consumption rates. Finally, HD striatal neurons expressing exogenous PGC-1alpha were resistant to 3-nitropropionic acid treatment. Altered PGC-1alpha function may thus link transcription dysregulation and mitochondrial dysfunction in HD.

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    • "Since the identification of peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) as a master regulator of mitochondrial biogenesis in brown adipose tissue (Puigserver et al., 1998), a number of studies have demonstrated an association between PGC-1α dysfunction and neurological disorders, including Huntington Disease (Cui et al., 2006; Weydt et al., 2006; Chaturvedi et al., 2010; Hathorn et al., 2011; Johri et al., 2012; Puddifoot et al., 2012; Soyal et al., 2012), Parkinson Disease (St- Pierre et al., 2006; Zheng et al., 2010; Clark et al., 2011; Shin et al., 2011; Thomas et al., 2012), and Alzheimer Disease (Qin et al., 2009; Sheng et al., 2012; Pedros et al., 2014). Germline (Lin et al., 2004; Leone et al., 2005; Lucas et al., 2012) and nervous system-specific (Lucas et al., 2012) deletion of PGC-1α causes pronounced neurodegeneration in brain regions involved in motor control and deficits in motor coordination, and PGC- 1α overexpression can promote neuronal survival and function in some mouse models (Cui et al., 2006; Mudo et al., 2012; Tsunemi et al., 2012). "
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    ABSTRACT: Alterations in the expression and activity of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (ppargc1a or PGC-1α) have been reported in multiple movement disorders, yet it is unclear how a lack of PGC-1α impacts transcription and function of the cerebellum, a region with high PGC-1α expression. We show here that mice lacking PGC-1α exhibit ataxia in addition to the previously described deficits in motor coordination. Using q-RT-PCR in cerebellar homogenates from PGC-1α −/− mice, we measured expression of 37 microarray-identified transcripts upregulated by PGC-1α in SH-SY5Y neuroblastoma cells with neuroanatomical overlap with PGC-1α or parvalbumin (PV), a calcium buffer highly expressed by Purkinje cells. We found significant reductions in transcripts with synaptic (complexin1, Cplx1; Pacsin2), structural (neurofilament heavy chain, Nefh), and metabolic (isocitrate dehydrogenase 3a, Idh3a; neutral cholesterol ester hydrolase 1, Nceh1; pyruvate dehydrogenase alpha 1, Pdha1; phytanoyl-CoA hydroxylase, Phyh; ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1, Uqcrfs1) functions. Using conditional deletion of PGC-1α in PV-positive neurons, we determined that 50% of PGC-1α expression and a reduction in a subset of these transcripts could be explained by its concentration in PV-positive neuronal populations in the cerbellum. To determine whether there were functional consequences associated with these changes, we conducted stereological counts and spike rate analysis in Purkinje cells, a cell type rich in PV, from PGC-1α −/− mice. We observed a significant loss of Purkinje cells by 6 weeks of age, and the remaining Purkinje cells exhibited a 50% reduction in spike rate. Together, these data highlight the complexity of PGC-1α's actions in the central nervous system and suggest that dysfunction in multiple cell types contribute to motor deficits in the context of PGC-1α deficiency.
    Frontiers in Cellular Neuroscience 01/2015; 8(441):1. DOI:10.3389/fncel.2014.00441 · 4.29 Impact Factor
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    • "Cox7c is described in the Alzheimer's disease pathway (ko05012) according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) (Kanehisa 2002). Thereby, it seems to be involved in mitochondrial dysfunction (Weydt et al. 2006), which is reported to be a prominent feature of AD (Wang et al. 2014). e470 maps to the second intron of lncRNA AI506816. "
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    ABSTRACT: We have generated a novel, neuro-specific ncRNA microarray, covering 1472 ncRNA species, to investigate their expression in different mouse models for central nervous system diseases. Thereby, we analyzed ncRNA expression in two mouse models with impaired calcium channel activity, implicated in Epilepsy or Parkinson's disease, respectively, as well as in a mouse model mimicking pathophysiological aspects of Alzheimer's disease. We identified well over a hundred differentially expressed ncRNAs, either from known classes of ncRNAs, such as miRNAs or snoRNAs or which represented entirely novel ncRNA species. Several differentially expressed ncRNAs in the calcium channel mouse models were assigned as miRNAs and target genes involved in calcium signaling, thus suggesting feedback regulation of miRNAs by calcium signaling. In the Alzheimer mouse model, we identified two snoRNAs, whose expression was deregulated prior to amyloid plaque formation. Interestingly, the presence of snoRNAs could be detected in cerebral spine fluid samples in humans, thus potentially serving as early diagnostic markers for Alzheimer's disease. In addition to known ncRNAs species, we also identified 63 differentially expressed, entirely novel ncRNA candidates, located in intronic or intergenic regions of the mouse genome, genomic locations, which previously have been shown to harbor the majority of functional ncRNAs.
    RNA 10/2014; 20(12). DOI:10.1261/rna.047225.114 · 4.94 Impact Factor
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    • "This is in line with phenotypes of other full-length models of HD, as the increased body weight of BACHD and YAC128 mice has been shown to at least in part be due to an increase in adipose tissue mass [28], [29]. It should be pointed out that R6/2 and N171-82Q mice, which only express a fragment of the disease-causing gene, also carry excess amounts of adipose tissue [25], [30]. R6/2 mice have further been shown to maintain this increased fat mass even when they start to lose weight [25]. "
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    ABSTRACT: Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.
    PLoS ONE 08/2014; 9(8):e105662. DOI:10.1371/journal.pone.0105662 · 3.23 Impact Factor
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