Transcriptional dysregulation in Huntington's disease: a failure of adaptive transcriptional homeostasis

Kumar, Amit; Vaish, Manisha; Ratan, Rajiv R.

doi:10.1016/j.drudis.2014.03.016

Cited by 56 publications

(54 citation statements)

References 68 publications

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“…Another theory of HD pathogenesis, which also intersects with cancer, has involved transcription deregulation. Kumar et al (2014) suggest that HD represents a neurodevelopmental disorder, product of the pathological disruption of evolutionarily preserved adaptive gene programs to offset oxidative stress, mitochondrial dysfunction, and accumulation of misfolded proteins. Transcriptional deregulation of adaptive genes is even more exacerbated by repression of genes involved in normal synaptic activity or growth factor signaling.…”

Section: Huntington's Diseasementioning

confidence: 99%

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions

Rojas

Cesarini

Etcheverry

et al. 2020

Journal of Integrative Neuroscience

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Several epidemiological studies support low cancer rates in patients with neurodegenerative disorders, including Parkinson's disease, Huntington's disease, and Alzheimer's disease. Different mechanisms were raised as possible causes, from mutated tumor suppressor genes (PARKIN, PINK1) to small interfering RNA based on the CAG trinucleotide repeat expansions located in introns or untranslated regions. However, as every rule has an exception, some tumors have an increased incidence in these neurodegenerative diseases such as breast and skin cancer (melanoma). This mini-review aims to establish the epidemiology between these neurodegenerative disorders and cancer to determine the possible mechanisms involved and therefore set eventual therapeutic applications. According to our findings, we conclude the presence of an inverse relationship among most cancers and the aforementioned neurodegenerative disorders. However, this concept needs to be considered cautiously considering specific genetic and extra-genetic linkage factors for particular tumors.

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Section: Huntington's Diseasementioning

confidence: 99%

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions

Rojas

Cesarini

Etcheverry

et al. 2020

Journal of Integrative Neuroscience

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“…Transcriptional profiling in human and HD mouse models have demonstrated a large number of genes that are dysregulated in HD (Hodges et al., ; Kuhn et al., ; Luthi‐Carter et al., ; Seredenina & Luthi‐Carter, ). Although mutant HTT plays the most important role in altered gene expression by interacting with and/or sequestering regulatory proteins of transcription (Kumar, Vaish, & Ratan, ; Sugars & Rubinsztein, ), alterations in signaling pathways cannot be ruled out as a possible mechanism of transcriptomic changes.…”

Section: Cellular and Molecular Changesmentioning

confidence: 99%

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

Rangel‐Barajas

Rebec

2018

CP Neuroscience

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Transgenic mouse models of Huntington's disease (HD), a neurodegenerative condition caused by a single gene mutation, have been transformative in their ability to reveal the molecular processes and pathophysiological mechanisms underlying the HD behavioral phenotype. Three model categories have been generated depending on the genetic context in which the mutation is expressed: truncated, full-length, and knock-in. No single model, however, broadly replicates the behavioral symptoms and massive neuronal loss that occur in human patients. The disparity between model and patient requires careful consideration of what each model has to offer when testing potential treatments. Although the translation of animal data to the clinic has been limited, each model can make unique contributions toward an improved understanding of the neurobehavioral underpinnings of HD. Thus, conclusions based on data obtained from more than one model are likely to have the most success in the search for new treatment targets. © 2018 by John Wiley & Sons, Inc.

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“…The mutated huntingtin, which is expressed in all tissues, causes central and peripheral tissue abnormalities . In conjunction with neurological impairments, HD patients show striking metabolic dysfunction, including weight loss, skeletal muscle wasting, impaired glucose metabolism and negative energy balance …”

Section: Introductionmentioning

confidence: 99%

Ghrelin‐mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington's disease

Rudenko

Springer

Skov

et al. 2019

J Neuroendocrinology

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Huntington's disease (HD) is a heritable neurodegenerative disorder, characterised by metabolic disturbances, along with cognitive and psychiatric impairments. Targeting metabolic HD dysfunction via the maintenance of body weight and fat mass and restoration of peripheral energy metabolism can improve the progression of neurological symptoms. In this respect, we focused on the therapeutic potential of the orexigenic peptide hormone ghrelin, which plays an important role in promoting a positive energy balance. In the present study, we found a significant disruption of circadian metabolic regulation in a R6/2 mouse HD model in the late stage of disease. Daily circadian rhythms of activity, energy expenditure, respiratory exchange ratio and feeding were strongly attenuated in R6/2 mice. During the rest phase, R6/2 mice had a higher total activity, elevated energy expenditure and excessive water consumption compared to control mice. We also found that, in the late stage of disease, R6/2 mice had ghrelin axis deficiency as a result of low circulating ghrelin levels, in addition to down‐regulation of the ghrelin receptor and several key signalling molecules in the hypothalamus, as well as a reduced responsiveness to exogenous peripheral ghrelin. We demonstrated that, in pre‐symptomatic mice, responsiveness to ghrelin is preserved. Chronic ghrelin treatment efficiently increased lean body mass and decreased the energy expenditure and fat utilisation of R6/2 mice in the early stage of disease. In addition, ghrelin treatment was also effective in the normalisation of drinking behaviour and the rest activity of these mice. Ghrelin treatment could provide a novel therapeutic possibility for delaying disease progression; however, deficiency in ghrelin receptor expression could limit its therapeutic potential in the late stage of disease.

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Transcriptional dysregulation in Huntington's disease: a failure of adaptive transcriptional homeostasis

Cited by 56 publications

References 68 publications

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

Ghrelin‐mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington's disease

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