Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism

Lee, Jong Min; Ivanova, Elena; Seong, Ihn Sik; Cashorali, Tanya; Kohane, Isaac S.; Gusella, James F.; MacDonald, Marcy E.

doi:10.1371/journal.pgen.0030135

Cited by 68 publications

(58 citation statements)

References 60 publications

(63 reference statements)

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“…There is also some evidence that mHtt can impair cellular bioenergetics by affecting extra-mitochondrial pathways. 9,10 In addition, expression of mHtt in non-neuronal cells such as astrocytes may also exacerbate HD neuropathology. [11][12][13][14][15] Astrocytes regulate energy metabolism by providing neuronal mitochondria with energy substrates derived from glycolysis.…”

Section: Introductionmentioning

confidence: 99%

Impaired Brain Energy Metabolism in the BACHD Mouse Model of Huntington's Disease: Critical Role of Astrocyte–Neuron Interactions

Boussicault

Hérard

Calingasan

et al. 2014

J Cereb Blood Flow Metab

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Huntington's disease (HD) is caused by cytosine-adenine-guanine (CAG) repeat expansions in the huntingtin (Htt) gene. Although early energy metabolic alterations in HD are likely to contribute to later neurodegenerative processes, the cellular and molecular mechanisms responsible for these metabolic alterations are not well characterized. Using the BACHD mice that express the full-length mutant huntingtin (mHtt) protein with 97 glutamine repeats, we first demonstrated localized in vivo changes in brain glucose use reminiscent of what is observed in premanifest HD carriers. Using biochemical, molecular, and functional analyses on different primary cell culture models from BACHD mice, we observed that mHtt does not directly affect metabolic activity in a cell autonomous manner. However, coculture of neurons with astrocytes from wild-type or BACHD mice identified mutant astrocytes as a source of adverse non-cell autonomous effects on neuron energy metabolism possibly by increasing oxidative stress. These results suggest that astrocyte-to-neuron signaling is involved in early energy metabolic alterations in HD.

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Section: Introductionmentioning

confidence: 99%

Impaired Brain Energy Metabolism in the BACHD Mouse Model of Huntington's Disease: Critical Role of Astrocyte–Neuron Interactions

Boussicault

Hérard

Calingasan

et al. 2014

J Cereb Blood Flow Metab

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“…Impairment of the ubiquitin-proteasome pathway has been reported in HD (Bennett et al, 2007). Transcriptional dysregulation has also been widely reported in HD (Cha, 2007) and specifically in the STHdh Q111/Q111 cells (Lee et al, 2007) and in the R6/2 mice (Crocker et al, 2006). We found that xCT mRNA expression is decreased in the STHdh Q111/Q111 cells (unpaired Student's t-test, t(7)=7.4, p<0.005; Mann-Whitney test, p<0.001) (Fig.…”

Section: Resultsmentioning

confidence: 92%

Dysregulation of system xc− expression induced by mutant huntingtin in a striatal neuronal cell line and in R6/2 mice

Frederick

Bertho

Patel

et al. 2014

Neurochemistry International

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Oxidative stress has been implicated in the pathogenesis of Huntington's disease (HD), however, the origin of the oxidative stress is unknown. System xc- plays a role in the import of cystine to synthesize the antioxidant glutathione. We found in the STHdhQ7/Q7 and STHdhQ111/Q111 striatal cell lines, derived from neuronal precursor cells isolated from knock-in mice containing 7 or 111 CAG repeats in the huntingtin gene, that there is a decrease in system xc- function. System xc- is composed of two proteins, the substrate specific transporter, xCT, and an anchoring protein, CD98. The decrease in function in system xc- that we observed is caused by a decrease in xCT mRNA and protein expression in the STHdhQ111/Q111 cells. In addition we found a decrease in protein and mRNA expression in the transgenic R6/2 HD mouse model at 6 weeks of age. STHdhQ111/Q111 cells have lower basal levels of GSH and higher basal levels of ROS. Acute inhibition of system xc- causes greater increase in oxidative stress in the STHdhQ111/Q111 cells than in the STHdhQ7/Q7 cells. These results suggest that a defect in the regulation of xCT may be involved in the pathogenesis of HD by compromising xCT expression and increasing susceptibility to oxidative stress.

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“…133 Defects in extra-mitochondrial energy metabolism have been observed in mouse striatal models of HD. 134 In addition to the potential mitochondrial dysfunction via decreased MnSOD discussed in the previous section, reductions in important metabolites necessary for the tricarboxylic acid (TCA) cycle can also lead to reduced mitochondrial respiration and ATP production. One important enzyme that produces metabolites for the TCA cycle is pyruvate carboxylase.…”

Section: Energeticsmentioning

confidence: 99%

“…Of note, gene expression profiling data from a striatal model of HD implicated several genes in glucose metabolism as being altered in HD; in particular, expression of PCX (the gene which encodes PC) is elevated in an HD mutant line. 134 Thus, models of both HD and manganese deficiency in rodents result in increased PC expression or activity.…”

Section: Energeticsmentioning

confidence: 99%

Manganese and Huntington Disease

Tidball¹,

Bichell²,

Bowman³

2014

Manganese in Health and Disease

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Huntington's disease (HD) is a devastating neurodegenerative disease presenting with impaired movement, psychological and behavioral disturbances, and cognitive decline. The most pronounced symptoms are motor impairments caused by degeneration of the medium spiny neurons of the caudate and putamen. Heavy metals are closely linked with both function and dysfunction in these basal ganglia nuclei, and are, therefore, likely candidates to be the environmental modifiers for age of onset in HD. HD patient cortices and mouse in vitro and in vivo models of HD have shown decreases in accumulation of manganese (Mn2+). Manganese is a necessary cofactor for several enzymes vital to proper cellular functioning, including arginase, manganese superoxide dismutase, glutamine synthetase, and pyruvate carboxylase. Additionally, manganese has also been shown to alter cellular signaling, particularly in the IGF–AKT and ATM–p53 pathways. Manganese deficiency can result in many dysfunctional manifestations similar to Huntington's disease, including urea cycle dysfunction, altered glutamate regulation, increased oxidative stress, and metabolic disturbances, in which these enzymatic functions are crucial. In this chapter, we elaborate on the potential influence of manganese and other metals in Huntington's disease; we also investigate the potential role of manganese-dependent enzymes in HD pathophysiology.

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Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism

Cited by 68 publications

References 60 publications

Impaired Brain Energy Metabolism in the BACHD Mouse Model of Huntington's Disease: Critical Role of Astrocyte–Neuron Interactions

Impaired Brain Energy Metabolism in the BACHD Mouse Model of Huntington's Disease: Critical Role of Astrocyte–Neuron Interactions

Dysregulation of system xc− expression induced by mutant huntingtin in a striatal neuronal cell line and in R6/2 mice

Manganese and Huntington Disease

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