mGluR5 regulates REST/NRSF signaling through N-cadherin/β-catenin complex in Huntington’s disease

Souza, Jéssica M. de; Abd-Elrahman, Khaled S.; Ribeiro, Fabíola M.; Ferguson, Stephen S. G.

doi:10.1186/s13041-020-00657-7

Cited by 22 publications

(12 citation statements)

References 62 publications

(106 reference statements)

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“…Alteration in protein sumoylation is a well described mechanism in HD, both for HTT itself, as well as in general [14-18]. Also, REST has been implicated in HD pathogenesis [19-21].…”

Section: Resultsmentioning

confidence: 99%

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

Neueder

Kojer

Hering

et al. 2022

Preprint

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Background: A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examined whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. Results: We generated large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients - those most likely involved in clinical trials. In-depth single nucleotide polymorphism data across the HTT gene will facilitate the use of the generated primary- and iPSC cell lines in allele-specific targeting approaches. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirmed the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observed changes in the homeostasis of extracellular vesicles, where we found consistent changes of genes and proteins involved in this process. Conclusions: Our 'omics data document the involvement of inflammation, energy metabolism and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. Together with the primary cell lines established from peripheral tissues and a large panel of iPSC lines that can serve as human models of HD, the generated data are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis.

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“…Alteration in protein sumoylation is a well described mechanism in HD, both for HTT itself, as well as in general [14-18]. Also, REST has been implicated in HD pathogenesis [19-21].…”

Section: Resultsmentioning

confidence: 99%

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

Neueder

Kojer

Hering

et al. 2022

Preprint

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“…We used four lineages in our study, including wild type (WT), mGluR5 −/− , BACHD, and the double mutant mice (BACHD/mGluR5 −/− ). For obtaining all genotypes, we performed the crossing in accordance to previous literature 35 . In summary, the first generation (F1) was originated by crossing over BACHD and mGluR5 −/− .…”

Section: Methodsmentioning

confidence: 99%

Metabotropic glutamate receptor 5 knockout rescues obesity phenotype in a mouse model of Huntington’s disease

Santos

Ribeiro

Ferreira-Vieira

et al. 2022

Sci Rep

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Obesity represents a global health problem and is characterized by metabolic dysfunctions and a low-grade chronic inflammatory state, which can increase the risk of comorbidities, such as atherosclerosis, diabetes and insulin resistance. Here we tested the hypothesis that the genetic deletion of metabotropic glutamate receptor 5 (mGluR5) may rescue metabolic and inflammatory features present in BACHD mice, a mouse model of Huntington’s disease (HD) with an obese phenotype. For that, we crossed BACHD and mGluR5 knockout mice (mGluR5−/−) in order to obtain the following groups: Wild type (WT), mGluR5−/−, BACHD and BACHD/mGluR5−/− (double mutant mice). Our results showed that the double mutant mice present decreased body weight as compared to BACHD mice in all tested ages and reduced visceral adiposity as compared to BACHD at 6 months of age. Additionally, 12-month-old double mutant mice present increased adipose tissue levels of adiponectin, decreased leptin levels, and increased IL-10/TNF ratio as compared to BACHD mice. Taken together, our preliminary data propose that the absence of mGluR5 reduce weight gain and visceral adiposity in BACHD mice, along with a decrease in the inflammatory state in the visceral adipose tissue (VAT), which may indicate that mGluR5 may play a role in adiposity modulation.

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“…We used four lineages in our study, including wild type (WT), mGluR5 -/ -, BACHD, and the double mutant mice (BACHD/mGluR5 -/ -). For obtaining all genotypes, we performed the crossing in accordance to previous literature 20 . In summary, the rst generation (F1) was originated by crossing over BACHD and mGluR5 -/ -.…”

Section: Methodsmentioning

confidence: 99%

Metabotropic Glutamate Receptor 5 Knockout Rescues Obesity Phenotype in a Mice Model of Huntington´s Disease

Santos¹,

Ribeiro²,

Vieira³

et al. 2021

Preprint

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Obesity represents a serious global public health problem and is characterized by a low-grade chronic inflammatory state, which can increase the risk of comorbidities, such as: atherosclerosis, diabetes and insulin resistance. In this study, we investigated the effects of the genetic deletion of the metabotropic glutamate receptor 5 (mGluR5) on the modulation of obesity features in BACHD mice, a mouse model of Huntington´s disease. For that, we crossed BACHD and mGluR5 knockout mice (mGluR5−/−) in order to obtain the following groups: Wild type (WT), mGluR5−/−, BACHD and BACHD/mGluR5−/− (double mutant mice). Our results showed that the double mutant mice present decreased body weight as compared to BACHD mice at all tested ages and reduced visceral adiposity as compared to BACHD mice at 6 and 12 months of age. Additionally, 12-month-old double mutant mice present increased adipose tissue levels of adiponectin, decreased leptin levels, and increased IL-10/TNF ratio as compared to BACHD mice. Taken together, our data propose that the absence of mGluR5 reduce weight gain and visceral adiposity in BACHD mice, along with a decrease in the inflammatory state in the visceral adipose tissue (VAT), which may indicate that mGluR5 may play a role in adiposity modulation.

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mGluR5 regulates REST/NRSF signaling through N-cadherin/β-catenin complex in Huntington’s disease

Cited by 22 publications

References 62 publications

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

Metabotropic glutamate receptor 5 knockout rescues obesity phenotype in a mouse model of Huntington’s disease

Metabotropic Glutamate Receptor 5 Knockout Rescues Obesity Phenotype in a Mice Model of Huntington´s Disease

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