<i>SIRT1</i> is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease

Baldo, Barbara; Gabery, Sanaz; Soylu-Kucharz, Rana; Cheong, Rachel Y.; Henningsen, Jo B; Englund, Elisabet; McLean, Catriona; Kirik, Deniz; Halliday, Glenda M.; Petersén, Åsa

doi:10.1111/nan.12514

Cited by 35 publications

(32 citation statements)

References 77 publications

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“…A recent study showed significant reduction of MCH mRNA levels in HD cases compared to controls although the number of MCH-immunopositive neurons is not affected [52]. Analyses of mRNA levels of other factors in the LHA in HD cases indicated that the dopamine D2-receptor (D2R) levels are also reduced [52]. mRNA levels of D2R are not reduced in other hypothalamic areas suggesting that the signal of D2R reductions detected using PET may arise from the LHA specifically.…”

Section: Neuropathological Changes In the Hypothalamus In Clinical Hdmentioning

confidence: 99%

“…Later studies established an important role for the LHA in the regulation of sleep, energy balance, reward and motivated behaviors [49]. In HD, there is a 38% reduction in the number of orexin (hypocretin) immunopositive-neurons in HD and mRNA levels are also diminished compared to control cases [35,[50][51][52]. Orexin is a neuropeptide that is only expressed in the LHA and it plays an important role in the regulation of sleep, emotion and metabolism [53,54].…”

Section: Neuropathological Changes In the Hypothalamus In Clinical Hdmentioning

confidence: 99%

“…Melanin-concentrating hormone (MCH) is another emotion-regulating neuropeptide that is expressed in neighboring neurons within the LHA [55]. A recent study showed significant reduction of MCH mRNA levels in HD cases compared to controls although the number of MCH-immunopositive neurons is not affected [52]. Analyses of mRNA levels of other factors in the LHA in HD cases indicated that the dopamine D2-receptor (D2R) levels are also reduced [52].…”

Section: Neuropathological Changes In the Hypothalamus In Clinical Hdmentioning

confidence: 99%

“…1, Table 1). A recent study showed reduced expression of mRNA levels of brain-derived neurotrophic factor (BDNF) in the VMH but not in the LHA, PVN or SON of HD cases compared to controls [52]. The VMH constitutes a group of cells involved in the regulation of energy homeostasis as well as aggression [58][59][60][61][62][63][64].…”

Section: Hypothalamic Gene Expression Changes In Clinical Hdmentioning

confidence: 99%

“…BDNF is expressed in the VMH [65] and reduced expression of BDNF in mice has been associated with aggressiveness, hyperphagia and obesity [66,67]. BDNF is well known to be reduced in the cerebral cortex in clinical HD and has been implicated in the pathogenesis in HD [52,68]. Hence, the effects of the BDNF system specifically in the VMH may also play a role in HD.…”

Section: Hypothalamic Gene Expression Changes In Clinical Hdmentioning

confidence: 99%

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The Role of Hypothalamic Pathology for Non-Motor Features of Huntington’s Disease

Cheong

Gabery

Petersén

2019

JHD

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Huntington's disease (HD) is a fatal genetic neurodegenerative disorder. It has mainly been considered a movement disorder with cognitive symptoms and these features have been associated with pathology of the striatum and cerebral cortex. Importantly, individuals with the mutant huntingtin gene suffer from a spectrum of non-motor features often decades before the motor disorder manifests. These symptoms and signs include a range of psychiatric symptoms, sleep problems and metabolic changes with weight loss particularly in later stages. A higher body mass index at diagnosis is associated with slower disease progression. The common psychiatric symptom of apathy progresses with the disease. The fact that non-motor features are present early in the disease and that they show an association to disease progression suggest that unravelling the underlying neurobiological mechanisms may uncover novel targets for early disease intervention and better symptomatic treatment. The hypothalamus and the limbic system are important brain regions that regulate emotion, social cognition, sleep and metabolism. A number of studies using neuroimaging, postmortem human tissue and genetic manipulation in animal models of the disease has collectively shown that the hypothalamus and the limbic system are affected in HD. These findings include the loss of neuropeptide-expressing neurons such as orexin (hypocretin), oxytocin, vasopressin, somatostatin and VIP, and increased levels of SIRT1 in distinct nuclei of the hypothalamus. This review provides a summary of the results obtained so far and highlights the potential importance of these changes for the understanding of non-motor features in HD.

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Section: Neuropathological Changes In the Hypothalamus In Clinical Hdmentioning

confidence: 99%

Section: Neuropathological Changes In the Hypothalamus In Clinical Hdmentioning

confidence: 99%

Section: Neuropathological Changes In the Hypothalamus In Clinical Hdmentioning

confidence: 99%

Section: Hypothalamic Gene Expression Changes In Clinical Hdmentioning

confidence: 99%

Section: Hypothalamic Gene Expression Changes In Clinical Hdmentioning

confidence: 99%

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The Role of Hypothalamic Pathology for Non-Motor Features of Huntington’s Disease

Cheong

Gabery

Petersén

2019

JHD

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Interaction between resveratrol and SIRT1: role in neurodegenerative diseases

Zhu,

Yang,

Fan

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Early white matter pathology in the fornix of the limbic system in Huntington disease

et al. 2021

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Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The typical motor symptoms have been associated with basal ganglia pathology. However, psychiatric and cognitive symptoms often precede the motor component and may be due to changes in the limbic system. Recent work has indicated pathology in the hypothalamus in HD but other parts of the limbic system have not been extensively studied. Emerging evidence suggests that changes in HD also include white matter pathology. Here we investigated if the main white matter tract of the limbic system, the fornix, is affected in HD. We demonstrate that the fornix is 34% smaller already in prodromal HD and 41% smaller in manifest HD compared to controls using volumetric analyses of MRI of the IMAGE-HD study. In post-mortem fornix tissue from HD cases, we confirm the smaller fornix volume in HD which is accompanied by signs of myelin breakdown and reduced levels of the transcription factor myelin regulating factor but detect no loss of oligodendrocytes. Further analyses using RNA-sequencing demonstrate downregulation of oligodendrocyte identity markers in the fornix of HD cases. Analysis of differentially expressed genes based on transcription-factor/target-gene interactions also revealed enrichment for binding sites of SUZ12 and EZH2, components of the Polycomb Repressive Complex 2, as well as RE1 Regulation Transcription Factor. Taken together, our data show that there is early white matter pathology of the fornix in the limbic system in HD likely due to a combination of reduction in oligodendrocyte genes and myelin break down.

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SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease

Abstract: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.

Cited by 35 publications

References 77 publications

The Role of Hypothalamic Pathology for Non-Motor Features of Huntington’s Disease

The Role of Hypothalamic Pathology for Non-Motor Features of Huntington’s Disease

Interaction between resveratrol and SIRT1: role in neurodegenerative diseases

Early white matter pathology in the fornix of the limbic system in Huntington disease

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