Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT

Moreno, Cesar; Ehrlich, Michelle E.; Mobbs, Charles V.

doi:10.1016/j.nbd.2015.09.012

Cited by 28 publications

(24 citation statements)

References 70 publications

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“…In addition, consistent with mutant Huntingtin accelerating cellular aging, a recent study reported an accumulation of epigenetic markers of aging in the brain of HD patients as compared to control subjects (Horvath et al, 2016). In line with this notion, several genetic, pharmacological and dietary anti-aging interventions have been reported to ameliorate aspects of HD in mouse models (Duan et al, 2003, Ma et al, 2007, Sadagurski et al, 2011, Tallaksen-Greene et al, 2014, Moreno et al, 2016). …”

Section: Discussionmentioning

confidence: 85%

Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport

Gasset-Rosa

Chillón-Marinas

Goginashvili

et al. 2017

Neuron

213

180

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Summary Onset of neurodegenerative disorders, including Huntington’s disease, is strongly influenced by aging. Hallmarks of aged cells include compromised nuclear envelope integrity, impaired nucleocytoplasmic transport, and accumulation of DNA double-strand breaks. We show that mutant huntingtin markedly accelerates all of these cellular phenotypes in a dose- and age-dependent manner in cortex and striatum of mice. Huntingtin-linked polyglutamine initially accumulates in nuclei, leading to disruption of nuclear envelope architecture, partial sequestration of factors essential for nucleocytoplasmic transport (Gle1 and RanGAP1), and intranuclear accumulation of mRNA. In aged mice, accumulation of RanGAP1 together with polyglutamine is shifted to perinuclear and cytoplasmic areas. Consistent with findings in mice, marked alterations in nuclear envelope morphology, abnormal localization of RanGAP1, and nuclear accumulation of mRNA were found in cortex of Huntington’s disease patients. Overall, our findings identify polyglutamine-dependent inhibition of nucleocytoplasmic transport and alteration of nuclear integrity as a central component of Huntington’s disease.

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Section: Discussionmentioning

confidence: 85%

Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport

Gasset-Rosa

Chillón-Marinas

Goginashvili

et al. 2017

Neuron

213

180

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“…More recently we have observed that dietary restriction induces hypothalamic Cbp in mice, associated with protective effects against proteotoxicity [9]. Similarly, dietary restriction in Caenorhabditis elegans induces Cbp , and blocking this induction prevents protective effects of dietary restriction during aging [8].…”

Section: Introductionmentioning

confidence: 99%

Role of Hypothalamic Creb-Binding Protein in Obesity and Molecular Reprogramming of Metabolic Substrates

et al. 2016

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We have reported a correlation between hypothalamic expression of Creb-binding protein (Cbp) and lifespan, and that inhibition of Cbp prevents protective effects of dietary restriction during aging, suggesting that hypothalamic Cbp plays a role in responses to nutritional status and energy balance. Recent GWAS and network analyses have also implicated Cbp as the most connected gene in protein-protein interactions in human Type 2 diabetes. The present studies address mechanisms mediating the role of Cbp in diabetes by inhibiting hypothalamic Cbp using a Cre-lox strategy. Inhibition of hypothalamic Cbp results in profound obesity and impaired glucose homeostasis, increased food intake, and decreased body temperature. In addition, these changes are accompanied by molecular evidence in the hypothalamus for impaired leptin and insulin signaling, a shift from glucose to lipid metabolism, and decreased Pomc mRNA, with no effect on locomotion. Further assessment of the significance of the metabolic switch demonstrated that enhanced expression of hypothalamic Cpt1a, which promotes lipid metabolism, similarly resulted in increased body weight and reduced Pomc mRNA.

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“…Subsequently we assessed the correlation of hypothalamic Cbp with the protective effects of dietary restriction in a mouse model of Huntington's disease [50]. In this case the model of dietary restriction was every-other-day feeding, which does not entail net reduction in caloric intake (mice consume twice as many calories on the ad lib fed days).…”

Section: Discussionmentioning

confidence: 99%

“…In this case the model of dietary restriction was every-other-day feeding, which does not entail net reduction in caloric intake (mice consume twice as many calories on the ad lib fed days). This protocol completely protected against the motor impairments produced by the transgenic expression of the mutant Huntington transgene, correlated with induction of Cbp in the hypothalamus [50]. The next most obvious study was to functionally assess if experimental inhibition of hypothalamic Cbp would prevent protective effects of dietary restriction.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms by Which the Ketogenic Diet Reverses Obesity and Diabetes

Moreno¹

2017

EMIJ

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Since the beginning of the 20th century, when low-carbohydrate diets were first implemented to treat Type 1 diabetes, the role of dietary composition in regulating glucose homeostasis and, increasingly, energy balance, has been the subject of great interest to both biomedical researchers and, increasingly, to the public. In fairly extreme circumstances (e.g., Type 1 diabetes untreated with insulin) low-carbohydrate diets (which are generally high-fat diets) can be useful to reduce blood glucose, but since the advent of insulin therapy, and increasing appreciation of the cardiovascular consequences of hyperlipidemia, clinical practice has dramatically favored highcarbohydrate, low-fat diets for diabetes (especially Type 2 diabetes, largely associated with obesity). This clinical advice, at the time, seemed fairly radical. In a famous treatise, "The Physiology of Taste" published in 1825, Brillat-Savarin, argue that consumption of "natural" diets (e.g., meat and vegetables) promote health, whereas "cultivated" diet (e.g., derived from rice and wheat) increasingly led to deterioration of health associated with affluence.Similarly, in 1837 Sylvester Graham published "A treatise on bread and breadmaking", essentially a tirade against food with grains (as well as meat), which were not suited to the assumption that gluttony was among the greatest sins (clearly a theme in subsequent American diet fads). Similarly throughout the 20th century popular diets (including those promotes by Adelle Davis in the 1950s, Robert Atkins in the 1970s, the paleo diet, and increasingly many more) have emphasized lowcarbohydrate, high-fat diets especially for weight loss (viewed by the public as a more compelling concern than glucose homeostasis). While these diets have little if any clinical evidence for efficacy, low-calorie, low-protein diets that produce ketogenesis are extremely effective to reverse obesity, hyperglycemia, and diabetic complications. The mini-review examines possible mechanisms mediating these remarkable effects, particularly focusing on epigenetic effects on hypothalamic neurons.

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Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT

Cited by 28 publications

References 70 publications

Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport

Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport

Role of Hypothalamic Creb-Binding Protein in Obesity and Molecular Reprogramming of Metabolic Substrates

Mechanisms by Which the Ketogenic Diet Reverses Obesity and Diabetes

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