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Revista de Neurologia Nov 2017Disorders affecting sleep and the circadian rhythm, autonomic clinical signs and symptoms, and neuroendocrine alterations are frequent characteristics in Huntington's... (Review)
Review
INTRODUCTION
Disorders affecting sleep and the circadian rhythm, autonomic clinical signs and symptoms, and neuroendocrine alterations are frequent characteristics in Huntington's disease, some of which present in early stages of the disease. It is reasonable to think that some of these features could result from a hypothalamic dysfunction affecting the centre regulating sleep, metabolism and the autonomic nervous system.
AIM
The study presents the evidence available to date that suggests the involvement of a hypothalamic disorder in Huntington's disease.
DEVELOPMENT
Histopathological, hormonal and neuroimaging research relates this area of the brain to Huntington's disease. The experimental findings and those obtained with animal models or in studies conducted with patients are summarised. Likewise, the clinical repercussions (sleep and circadian rhythm disorders, psychiatric and cognitive pathologies, and the clinical signs and symptoms linked to autonomic dysfunction) secondary to possible involvement of the hypothalamus in this disease are also described.
CONCLUSIONS
The hypothalamus acts as a centre that integrates the neuroendocrine and autonomic functions, and plays a significant role in cognitive and behavioural signs and symptoms. Disorders of this type have been highlighted in Huntington's disease. Further studies are needed to elucidate the role and scope of this region of the brain in this disease.
Topics: Humans; Huntington Disease; Hypothalamic Diseases; Neurosecretory Systems
PubMed: 29071701
DOI: No ID Found -
Journal of Huntington's Disease Oct 2016Redox homeostasis is crucial for proper cellular functions, including receptor tyrosine kinase signaling, protein folding, and xenobiotic detoxification. Under basal... (Review)
Review
Redox homeostasis is crucial for proper cellular functions, including receptor tyrosine kinase signaling, protein folding, and xenobiotic detoxification. Under basal conditions, there is a balance between oxidants and antioxidants. This balance facilitates the ability of oxidants, such as reactive oxygen species, to play critical regulatory functions through a direct modification of a small number of amino acids (e.g. cysteine) on signaling proteins. These signaling functions leverage tight spatial, amplitude, and temporal control of oxidant concentrations. However, when oxidants overwhelm the antioxidant capacity, they lead to a harmful condition of oxidative stress. Oxidative stress has long been held to be one of the key players in disease progression for Huntington's disease (HD). In this review, we will critically review this evidence, drawing some intermediate conclusions, and ultimately provide a framework for thinking about the role of oxidative stress in the pathophysiology of HD.
Topics: Humans; Huntington Disease; Oxidative Stress
PubMed: 27662334
DOI: 10.3233/JHD-160205 -
Journal of Neurochemistry Aug 2019Huntington disease (HD) is an inherited neurodegenerative disorder caused by an expansion of the CAG repeat region in the first exon of the huntingtin gene.... (Review)
Review
Huntington disease (HD) is an inherited neurodegenerative disorder caused by an expansion of the CAG repeat region in the first exon of the huntingtin gene. Neurodegeneration, which begins in the striatum and then spreads to other brain areas, is preceded by dysfunction in multiple aspects of neurotransmission across a variety of brain areas. This review will provide an overview of the neurochemical mediators and modulators of synaptic transmission that are disrupted in HD. This includes classical neurotransmitters like glutamate and gamma-aminobutyric acid, modulators such as dopamine, adenosine and endocannabinoids, and molecules like brain-derived neurotrophic factor which affect neurotransmission in a more indirect manner. Alterations in the functioning of these signaling pathways can occur across multiple brain regions such as striatum, cortex and hippocampus, and affect transmission and plasticity at the synapses within these regions, which may ultimately change behaviour and contribute to the pathophysiology of HD. The current state of knowledge in this area has already yielded useful information about the causes of synaptic dysfunction and selective cell death. A full understanding of the mechanisms and consequences of disruptions in synaptic function and plasticity will lend insight into the development of the symptoms of HD, and potential drug targets for ameliorating them.
Topics: Animals; Humans; Huntington Disease; Neuronal Plasticity; Synaptic Transmission
PubMed: 31095731
DOI: 10.1111/jnc.14723 -
International Journal of Molecular... Nov 2021Methylation of cytosine in CpG dinucleotides is the major DNA modification in mammalian cells that is a key component of stable epigenetic marks. This modification,... (Review)
Review
Methylation of cytosine in CpG dinucleotides is the major DNA modification in mammalian cells that is a key component of stable epigenetic marks. This modification, which on the one hand is reversible, while on the other hand, can be maintained through successive rounds of replication plays roles in gene regulation, genome maintenance, transgenerational epigenetic inheritance, and imprinting. Disturbed DNA methylation contributes to a wide array of human diseases from single-gene disorders to sporadic metabolic diseases or cancer. DNA methylation was also shown to affect several neurodegenerative disorders, including Huntington's disease (HD), a fatal, monogenic inherited disease. HD is caused by a polyglutamine repeat expansion in the Huntingtin protein that brings about a multifaceted pathogenesis affecting several cellular processes. Research of the last decade found complex, genome-wide DNA methylation changes in HD pathogenesis that modulate transcriptional activity and genome stability. This article reviews current evidence that sheds light on the role of DNA methylation in HD.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Humans; Huntingtin Protein; Huntington Disease; Protein Processing, Post-Translational
PubMed: 34884540
DOI: 10.3390/ijms222312736 -
Journal of Huntington's Disease 2021DNA damage repair (DDR) mechanisms have been implicated in a number of neurodegenerative diseases (both genetically determined and sporadic). Consistent with this,... (Review)
Review
DNA damage repair (DDR) mechanisms have been implicated in a number of neurodegenerative diseases (both genetically determined and sporadic). Consistent with this, recent genome-wide association studies in Huntington's disease (HD) and other trinucleotide repeat expansion diseases have highlighted genes involved in DDR mechanisms as modifiers for age of onset, rate of progression and somatic instability. At least some clinical genetic modifiers have been shown to have a role in modulating trinucleotide repeat expansion biology and could therefore provide new disease-modifying therapeutic targets. In this review, we focus on key considerations with respect to drug discovery and development using DDR mechanisms as a target for trinucleotide repeat expansion diseases. Six areas are covered with specific reference to DDR and HD: 1) Target identification and validation; 2) Candidate selection including therapeutic modality and delivery; 3) Target drug exposure with particular focus on blood-brain barrier penetration, engagement and expression of pharmacology; 4) Safety; 5) Preclinical models as predictors of therapeutic efficacy; 6) Clinical outcome measures including biomarkers.
Topics: Animals; DNA Damage; DNA Mismatch Repair; Drug Development; Drug Discovery; Humans; Huntingtin Protein; Huntington Disease; Trinucleotide Repeat Expansion
PubMed: 32925081
DOI: 10.3233/JHD-200421 -
Tidsskrift For Den Norske Laegeforening... Oct 2008Huntington's disease is an autosomal dominant slowly degenerative apoptotic condition in CNS, in particular in striatum. It is characterized by involuntary movements; in... (Review)
Review
Huntington's disease is an autosomal dominant slowly degenerative apoptotic condition in CNS, in particular in striatum. It is characterized by involuntary movements; in particular chorea, personality changes and subcortical dementia. About 250 persons are diagnosed in Norway with the condition at any time, most are diagnosed between 35 and 55 years but onset before 20 years of age can be seen and diagnosis in later life is not rare. The average duration is about 15 years from diagnosis to death, but it can be considerably longer. Signs, symptoms and therapeutic challenges are mentioned in addition to molecular and clinical genetic aspects, in particular pre-symptomatic and prenatal diagnosis.
Topics: Adult; Humans; Huntington Disease; Middle Aged; Prenatal Diagnosis; Prognosis
PubMed: 18846148
DOI: No ID Found -
Journal of Huntington's Disease 2017Huntingtin (HTT) is an essential protein during early embryogenesis and the development of the central nervous system (CNS). Conditional knock-out of mouse Huntingtin... (Review)
Review
Huntingtin (HTT) is an essential protein during early embryogenesis and the development of the central nervous system (CNS). Conditional knock-out of mouse Huntingtin (Htt) expression in the CNS beginning during neural development, as well as reducing Htt expression only during embryonic and early postnatal stages, results in neurodegeneration in the adult brain. These findings suggest that HTT is important for the development and/or maintenance of the CNS, but they do not address the question of whether HTT is required specifically in the adult CNS for its normal functions and/or homeostasis. Recently, it was reported that although removing Htt expression in young adult mice causes lethality due to acute pancreatitis, loss of Htt expression in the adult brain is well tolerated and does not result in either motor deficits or neurodegeneration for up to 7 months after Htt inactivation. However, recent studies have also demonstrated that HTT participates in several cellular functions that are important for neuronal homeostasis and survival including sensing reactive oxygen species (ROS), DNA damage repair, and stress responses, in addition to its role in selective macroautophagy. In this review, HTT's functions in development and in the adult CNS will be discussed in the context of these recent discoveries, together with a discussion of their potential impact on the design of therapeutic strategies for Huntington's disease (HD) aimed at lowering total HTT expression.
Topics: Animals; Brain; Humans; Huntingtin Protein; Huntington Disease
PubMed: 28339401
DOI: 10.3233/JHD-170235 -
Translational Neurodegeneration Apr 2024Huntington's disease (HD) is a devastating neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein, resulting from a CAG repeat... (Review)
Review
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein, resulting from a CAG repeat expansion in the huntingtin gene HTT. HD is characterized by a variety of debilitating symptoms including involuntary movements, cognitive impairment, and psychiatric disturbances. Despite considerable efforts, effective disease-modifying treatments for HD remain elusive, necessitating exploration of novel therapeutic approaches, including lifestyle modifications that could delay symptom onset and disease progression. Recent studies suggest that time-restricted eating (TRE), a form of intermittent fasting involving daily caloric intake within a limited time window, may hold promise in the treatment of neurodegenerative diseases, including HD. TRE has been shown to improve mitochondrial function, upregulate autophagy, reduce oxidative stress, regulate the sleep-wake cycle, and enhance cognitive function. In this review, we explore the potential therapeutic role of TRE in HD, focusing on its underlying physiological mechanisms. We discuss how TRE might enhance the clearance of mHTT, recover striatal brain-derived neurotrophic factor levels, improve mitochondrial function and stress-response pathways, and synchronize circadian rhythm activity. Understanding these mechanisms is critical for the development of targeted lifestyle interventions to mitigate HD pathology and improve patient outcomes. While the potential benefits of TRE in HD animal models are encouraging, future comprehensive clinical trials will be necessary to evaluate its safety, feasibility, and efficacy in persons with HD.
Topics: Animals; Humans; Huntington Disease; Fasting; Neurodegenerative Diseases; Oxidative Stress
PubMed: 38561866
DOI: 10.1186/s40035-024-00406-z -
Tremor and Other Hyperkinetic Movements... 2019Huntington's disease (HD) is a rare, progressive neurodegenerative disease. Currently, there is no cure for the disease, but treatment may alleviate HD symptoms. In... (Review)
Review
BACKGROUND
Huntington's disease (HD) is a rare, progressive neurodegenerative disease. Currently, there is no cure for the disease, but treatment may alleviate HD symptoms. In recent years, several exercise training interventions have been conducted in HD patients. In the current article, we review previous studies investigating targeted exercise training interventions in HD patients.
METHODS
We performed a literature search using the PubMed, Scopus, Web of Science, and Google Scholar databases on exercise training interventions in HD patients. Six publications fulfilled the criteria and were included in the review.
RESULTS
Exercise training resulted in beneficial effects on cardiovascular and mitochondrial function. Training effects on cognition, motor function, and body composition were less congruent, but a positive effect seems likely. Health-related quality of life during the training interventions was stable. Most studies reported no related adverse events in response to training.
DISCUSSION
Exercise training seems to be safe and feasible in HD patients. However, current knowledge is mainly based on short, small-scale studies and it cannot be transferred to all HD patients. Therefore, longer-term interventions with larger HD patient cohorts are necessary to draw firm conclusions about the potentially positive effects of exercise training in HD patients.
Topics: Animals; Exercise; Exercise Therapy; Humans; Huntington Disease
PubMed: 30783551
DOI: 10.7916/tm9j-f874 -
International Journal of Molecular... Feb 2021Among the main challenges in further advancing therapeutic strategies for Huntington's disease (HD) is the development of biomarkers which must be applied to assess the... (Review)
Review
Among the main challenges in further advancing therapeutic strategies for Huntington's disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders.
Topics: Biomarkers; Clinical Decision-Making; Disease Management; Disease Progression; Humans; Huntingtin Protein; Huntington Disease; Mutation; Oxidative Stress; Prognosis; RNA, Messenger
PubMed: 33557131
DOI: 10.3390/ijms22041561