Euglycemic Agent-mediated Hypothalamic Transcriptomic Manipulation in the N171–82Q Model of Huntington Disease Is Related to Their Physiological Efficacy

Martin, Bronwen; Chadwick, Wayne; Wang, Cong; Pantaleo, Nick; Daimon, Caitlin M.; Golden, Erin; Becker, Kevin G.; Wood, William H.; Carlson, Olga D.; Egan, Josephine M.; Maudsley, Stuart

doi:10.1074/jbc.m112.387316

Cited by 30 publications

(23 citation statements)

References 54 publications

(75 reference statements)

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“…On the other hand, Huntington's disease (HD), an autosomal and dominantly inherited neurodegenerative disorder characterized by neurological and cognitive symptoms, is accompanied by severe weight loss and metabolic abnormalities [12,13]. Impaired mitochondrial and energy metabolism, and a consequent negative energy balance, may contribute to the enhanced oxidative damage in HD pathogenesis [14,15].…”

Section: Introductionmentioning

confidence: 99%

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

et al. 2016

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Different factors may contribute to the development of neurodegenerative diseases. Among them, metabolic syndrome (MS), which has reached epidemic proportions, has emerged as a potential element that may be involved in neurodegeneration. Furthermore, studies have shown the importance of the sirtuin family in neuronal survival and MS, which opens the possibility of new pharmacological targets. This study investigates the influence of sirtuin metabolic pathways by examining the functional capacities of glucose-induced obesity in an excitotoxic state induced by a quinolinic acid (QA) animal model. Mice were divided into two groups that received different diets for 8 weeks: one group received a regular diet, and the other group received a high-fat diet (HF) to induce MS. The animals were submitted to a stereotaxic surgery and subdivided into four groups: Standard (ST), Standard-QA (ST-QA), HF and HF-QA. The QA groups were given a 250 nL quinolinic acid injection in the right striatum and PBS was injected in the other groups. Obese mice presented with a weight gain of 40 % more than the ST group beyond acquiring an insulin resistance. QA induced motor impairment and neurodegeneration in both ST-QA and HF-QA, although no difference was observed between these groups. The HF-QA group showed a reduction in adiposity when compared with the groups that received PBS. Therefore, the HF-QA group demonstrated a commitment-dependent metabolic pathway. The results suggest that an obesogenic diet does not aggravate the neurodegeneration induced by QA. However, the excitotoxicity induced by QA promotes a sirtuin pathway impairment that contributes to metabolic changes.

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Section: Introductionmentioning

confidence: 99%

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

et al. 2016

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“…RNA isolation from three individual animals in each experimental group was carried out using a Qiagen RNeasy Mini Kit (Qiagen, Inc., Valencia, CA), as described previously (Gesty-Palmer et al, 2013). RNA conversion to cDNA and subsequent hybridization with Sentrix MouseRef-8 Expression BeadChips (Illumina, San Diego, CA) was performed as described previously (Chadwick et al, 2010;Martin et al, 2012a). Microarray data were analyzed using DIANE 6.0 (http://www.…”

Section: Methodsmentioning

confidence: 99%

Delineation of a Conserved Arrestin-Biased Signaling Repertoire In Vivo

et al. 2015

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Biased G protein-coupled receptor agonists engender a restricted repertoire of downstream events from their cognate receptors, permitting them to produce mixed agonist-antagonist effects in vivo. While this opens the possibility of novel therapeutics, it complicates rational drug design, since the in vivo response to a biased agonist cannot be reliably predicted from its in cellula efficacy. We have employed novel informatic approaches to characterize the in vivo transcriptomic signature of the arrestin pathway-selective parathyroid hormone analog [D-Trp ]bovine PTH(7-34) elicits a distinctive arrestinsignaling focused transcriptomic response that is more coherently regulated across tissues than that of the pluripotent agonist, human PTH(1-34). This arrestin-focused network is closely associated with transcriptional control of cell growth and development. Our demonstration of a conserved arrestin-dependent transcriptomic signature suggests a framework within which the in vivo outcomes of arrestin-biased signaling may be generalized.

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“…We have previously identified the hypothalamus as one of the most important physiological loci for both aging and neurodegenerative activities (Chadwick et al, 2012; Martin et al, 2012b). In the current study, we employed hypothalamic gene transcriptomic data from wildtype mice, of both genders, across a broad age range (6, 12, 18 months) (Figure 2; Tables S2–S4 Female, Tables S5–S7 Male).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, at the present time, with the creation of high-dimensionality data analyzers, such as Plurigon , Ggobi and Iris following the widespread implementation of mass data collection pipelines (genome/proteome-wide), we may soon see the generation of highly predictive and nuanced structure-activity-relationships (SAR) specifically modeled against pathophysiological scenarios. We have already pioneered this approach, in a considerably low-scale manner, for the discovery and whole-animal SAR analysis of palliative agents for Huntington's disease (Martin et al, 2012b). In this study we were able to predict whole-animal therapeutic efficacy (using multiple biomedical indices) from complementary pathophysiological-pharmacogenomic-pattern investigation.…”

Section: Discussionmentioning

confidence: 99%

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Plurigon: three dimensional visualization and classification of high-dimensionality data

et al. 2013

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High-dimensionality data is rapidly becoming the norm for biomedical sciences and many other analytical disciplines. Not only is the collection and processing time for such data becoming problematic, but it has become increasingly difficult to form a comprehensive appreciation of high-dimensionality data. Though data analysis methods for coping with multivariate data are well-documented in technical fields such as computer science, little effort is currently being expended to condense data vectors that exist beyond the realm of physical space into an easily interpretable and aesthetic form. To address this important need, we have developed Plurigon, a data visualization and classification tool for the integration of high-dimensionality visualization algorithms with a user-friendly, interactive graphical interface. Unlike existing data visualization methods, which are focused on an ensemble of data points, Plurigon places a strong emphasis upon the visualization of a single data point and its determining characteristics. Multivariate data vectors are represented in the form of a deformed sphere with a distinct topology of hills, valleys, plateaus, peaks, and crevices. The gestalt structure of the resultant Plurigon object generates an easily-appreciable model. User interaction with the Plurigon is extensive; zoom, rotation, axial and vector display, feature extraction, and anaglyph stereoscopy are currently supported. With Plurigon and its ability to analyze high-complexity data, we hope to see a unification of biomedical and computational sciences as well as practical applications in a wide array of scientific disciplines. Increased accessibility to the analysis of high-dimensionality data may increase the number of new discoveries and breakthroughs, ranging from drug screening to disease diagnosis to medical literature mining.

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Euglycemic Agent-mediated Hypothalamic Transcriptomic Manipulation in the N171–82Q Model of Huntington Disease Is Related to Their Physiological Efficacy

Cited by 30 publications

References 54 publications

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

Delineation of a Conserved Arrestin-Biased Signaling Repertoire In Vivo

Plurigon: three dimensional visualization and classification of high-dimensionality data

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