Journal of Huntington's disease最新文献

Sleep and circadian disruption affects most individuals with Huntington's disease (HD) at some stage in their lives. Sleep and circadian dysregulation are also present in many mouse and the sheep models of HD. Here I review evidence for sleep and/or circadian dysfunction in HD transgenic animal models and discuss two key questions: 1) How relevant are such findings to people with HD, and 2) Whether or not therapeutic interventions that ameliorate deficits in animal models of HD might translate to meaningful therapies for people with HD.

Incidence of cancer is markedly reduced in patients with the hereditary neurodegenerative polyglutamine (polyQ) diseases. We have very poor knowledge of the underlying molecular mechanisms, but the expanded polyQ sequence is assumed to play a central role, because it is common to the respective disease related proteins. The inhibition seems to take place in all kinds of cells, because the lower cancer frequency applies to nearly all types of tumors and is not related with the characteristic pathological changes in specific brain tissues. Further, the cancer repressing mechanisms appear to be active early in life including in pre-symptomatic and early phase polyQ patients. Autophagy plays a central role in clearing proteins with expanded polyQ tracts, and autophagy modulation has been demonstrated and particularly investigated in Huntington's disease (HD). Macroautophagy may be dysfunctional due to defects in several steps of the process, whereas increased chaperone-mediated autophagy (CMA) has been shown in HD patients, cell and animal models. Recently, CMA is assumed to play a key role in prevention of cellular transformation of normal cells into cancer cells. Investigations of normal cells from HD and other polyQ carriers could therefore add further insight into the protective mechanisms of CMA in tumorigenesis, and be important for development of autophagy based strategies to prevent malignant processes leading to cancer and neurodegeneration.

Sleep occupies a peculiar place in our lives and in science, being both eminently familiar and profoundly enigmatic. Historically, philosophers, scientists and artists questioned the meaning and purpose of sleep. If Shakespeare's verses from MacBeth depicting "Sleep that soothes away all our worries" and "relieves the weary laborer and heals hurt minds" perfectly epitomize the alleviating benefits of sleep, it is only during the last two decades that the growing understanding of the sophisticated sleep regulatory mechanisms allows us to glimpse putative biological functions of sleep. Sleep control brings into play various brain-wide processes occurring at the molecular, cellular, circuit, and system levels, some of them overlapping with a number of disease-signaling pathways. Pathogenic processes, including mood disorders (e.g., major depression) and neurodegenerative illnesses such Huntington's or Alzheimer's diseases, can therefore affect sleep-modulating networks which disrupt the sleep-wake architecture, whereas sleep disturbances may also trigger various brain disorders. In this review, we describe the mechanisms underlying sleep regulation and the main hypotheses drawn about its functions. Comprehending sleep physiological orchestration and functions could ultimately help deliver better treatments for people living with neurodegenerative diseases.

Background: Huntingtin (htt) protein is an essential regulator of nervous system function through its various neuroprotective and pro-survival functions, and loss of wild-type htt function is implicated in the etiology of Huntington's disease. While its pathological role is typically understood as a toxic gain-of-function, some neuronal phenotypes also result from htt loss. Therefore, it is important to understand possible roles for htt in other physiological circumstances.

Objective: To elucidate the role of htt in the context of ethanol exposure, we investigated how loss of htt impacts behavioral and physiological responses to ethanol in Drosophila.

Methods: We tested flies lacking htt for ethanol sensitivity and tolerance, preference for ethanol using capillary feeder assays, and recovery of mobility after intoxication. Levels of dopamine neurotransmitter and numbers of dopaminergic cells in brains lacking dhtt were also measured.

Results: We found that dhtt-null flies are both less sensitive and more tolerant to ethanol exposure in adulthood. Moreover, flies lacking dhtt are more averse to alcohol than controls, and they recover mobility faster following acute ethanol intoxication. We showed that dhtt mediates these effects at least in part through the dopaminergic system, as dhtt is required to maintain normal levels of dopamine in the brain and normal numbers of dopaminergic cells in the adult protocerebrum.

Conclusions: Our results demonstrate that htt regulates the physiological response to ethanol and indicate a novel neuroprotective role for htt in the dopaminergic system, raising the possibility that it may be involved more generally in the response to toxic stimuli.

Sleep disorders are common in Huntington's disease (HD) but are complex; their bi-directional associations with psychiatric, cognitive, and motor dysfunction makes them especially important to both consider and to treat. The author provides a perspective in brief regarding sleep disturbances in HD, based on her experience caring for, and learning from, patients with HD for more than twenty years.

Background: Metabolic abnormalities have long been predicted in Huntington's disease (HD) but remain poorly characterized. Chronobiological dysregulation has been described in HD and may include abnormalities in circadian-driven metabolism.

Objective: Here we investigated metabolite profiles in the transgenic sheep model of HD (OVT73) at presymptomatic ages. Our goal was to understand changes to the metabolome as well as potential metabolite rhythm changes associated with HD.

Methods: We used targeted liquid chromatography mass spectrometry (LC-MS) metabolomics to analyze metabolites in plasma samples taken from female HD transgenic and normal (control) sheep aged 5 and 7 years. Samples were taken hourly across a 27-h period. The resulting dataset was investigated by machine learning and chronobiological analysis.

Results: The metabolic profiles of HD and control sheep were separable by machine learning at both ages. We found both absolute and rhythmic differences in metabolites in HD compared to control sheep at 5 years of age. An increase in both the number of disturbed metabolites and the magnitude of change of acrophase (the time at which the rhythms peak) was seen in samples from 7-year-old HD compared to control sheep. There were striking similarities between the dysregulated metabolites identified in HD sheep and human patients (notably of phosphatidylcholines, amino acids, urea, and threonine).

Conclusion: This work provides the first integrated analysis of changes in metabolism and circadian rhythmicity of metabolites in a large animal model of presymptomatic HD.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The disease, characterized by motor, cognitive, and psychiatric impairments, is caused by the expansion of a CAG repeat in the huntingtin gene. Despite the discovery of the mutation in 1993, no disease-modifying treatments are yet available. Understanding the molecular and cellular mechanisms involved in HD is therefore crucial for the development of novel treatments. Emerging research has found that HD might be classified as a secondary tauopathy, with the presence of tau insoluble aggregates in late HD. Increased total tau protein levels have been observed in both HD patients and animal models of HD. Tau hyperphosphorylation, the main feature of tau pathology, has also been investigated and our own published results suggest that the protein phosphorylation machinery is dysregulated in the early stages of HD in R6/1 transgenic mice, primarily in the cortex and striatum. Protein phosphorylation, catalysed by kinases, regulates numerous cellular mechanisms and has been shown to be dysregulated in other neurodegenerative disorders, including Alzheimer's disease. While it is still unclear how the mutation in the huntingtin gene leads to tau dysregulation in HD, several hypotheses have been explored. Evidence suggests that the mutant huntingtin does not directly interact with tau, but instead interacts with tau kinases, phosphatases, and proteins involved in tau alternative splicing, which could result in tau dysregulation as observed in HD. Altogether, there is increasing evidence that tau is undergoing pathological changes in HD and may be a good therapeutic target.

Background: Gastrointestinal symptoms are clinical features of Huntington's disease (HD), which adversely affect people's quality of life. We recently reported the first evidence of gut dysbiosis in HD gene expansion carriers (HDGECs). Here, we report on a randomized controlled clinical trial of a 6-week probiotic intervention in HDGECs.

Objective: The primary objective was to determine whether probiotics improved gut microbiome composition in terms of richness, evenness, structure, and diversity of functional pathways and enzymes. Exploratory objectives were to determine whether probiotic supplementation improved cognition, mood, and gastrointestinal symptoms.

Methods: Forty-one HDGECs, including 19 early manifest and 22 premanifest HDGECs were compared with 36 matched-healthy controls (HCs). Participants were randomly assigned probiotics or placebo and provided fecal samples at baseline and 6-week follow-up, which were sequenced using 16S-V3-V4 rRNA to characterize the gut microbiome. Participants completed a battery of cognitive tests and self-report questionnaires measuring mood and gastrointestinal symptoms.

Results: HDGECs had altered gut microbiome diversity when compared to HCs, indicating gut dysbiosis. Probiotic intervention did not ameliorate gut dysbiosis or have any effect on cognition, mood, or gastrointestinal symptoms. Gut microbiome differences between HDGECs and HCs were unchanged across time points, suggesting consistency of gut microbiome differences within groups.

Conclusion: Despite the lack of probiotic effects in this trial, the potential utility of the gut as a therapeutic target in HD should continue to be explored given the clinical symptomology, gut dysbiosis, and positive results from probiotics and other gut interventions in similar neurodegenerative diseases.