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Brain Research May 2016Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. The disease... (Review)
Review
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. The disease generally manifests in middle age with both physical and mental symptoms. There are no effective treatments or cures and death usually occurs 10-20 years after initial symptoms. Since the original identification of the Huntington disease associated gene, in 1993, a variety of models have been created and used to advance our understanding of HD. The most recent advances have utilized stem cell models derived from HD-patient induced pluripotent stem cells (iPSCs) offering a variety of screening and model options that were not previously available. The discovery and advancement of technology to make human iPSCs has allowed for a more thorough characterization of human HD on a cellular and developmental level. The interaction between the genome editing and the stem cell fields promises to further expand the variety of HD cellular models available for researchers. In this review, we will discuss the history of Huntington's disease models, common screening assays, currently available models and future directions for modeling HD using iPSCs-derived from HD patients. This article is part of a Special Issue entitled SI: PSC and the brain.
Topics: Animals; Cell Line; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Huntington Disease; Induced Pluripotent Stem Cells
PubMed: 26428226
DOI: 10.1016/j.brainres.2015.09.020 -
International Journal of Experimental... Apr 2019Dystonia associated with Huntington's disease, Parkinson's disease or other neurodegenerative diseases substantially affects patients' quality of life and is a major... (Review)
Review
Dystonia associated with Huntington's disease, Parkinson's disease or other neurodegenerative diseases substantially affects patients' quality of life and is a major health problem worldwide. The above-mentioned diseases are characterized by neurodegeneration accompanied by motor and cognitive impairment and often have complex aetiology. A frequent feature of these conditions is the abnormal accumulation of protein aggregates within specific neuronal populations in the affected brain regions. Familial neurodegenerative diseases are associated with a number of genetic mutations. Identification of these mutations allowed creation of modern model systems for studying neurodegeneration, either in cultured cells or in model animals. Animal models, especially mouse models, have contributed considerably to improving our understanding of the pathophysiology of neurodegenerative diseases. These models have allowed study of the pathogenic mechanisms and development of new disease-modifying strategies and therapeutic approaches. However, due to the complex nature of these pathologies and the irreversible damage that they cause to the neural tissue, effective therapies against neurodegeneration remain to be elaborated. In this review, we provide an overview of cellular and animal models developed for studying neurodegenerative diseases, including Huntington's disease and dystonia of different origins.
Topics: Animal Testing Alternatives; Animals; Cells, Cultured; Disease Models, Animal; Dystonia; Humans; Huntington Disease; Mice, Transgenic; Mutation; Rats, Transgenic
PubMed: 31090117
DOI: 10.1111/iep.12320 -
Journal of Huntington's Disease 2016Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study... (Review)
Review
Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study neurodegenerative diseases and identify biomarkers to facilitate the development of novel therapeutics. Many such CSF biomarkers have been proposed for Huntington's disease (HD) but none has been validated for clinical trial use. Across many studies proposing dozens of biomarker candidates, there is a notable lack of statistical power, consistency, rigor and validation. Here we review proposed CSF biomarkers including neurotransmitters, transglutaminase activity, kynurenine pathway metabolites, oxidative stress markers, inflammatory markers, neuroendocrine markers, protein markers of neuronal death, proteomic approaches and mutant huntingtin protein itself. We reflect on the need for large-scale, standardized CSF collections with detailed phenotypic data to validate and qualify much-needed CSF biomarkers for clinical trial use in HD.
Topics: Animals; Biomarkers; Biomedical Research; Disease Models, Animal; Humans; Huntington Disease; Mice
PubMed: 27031730
DOI: 10.3233/JHD-160196 -
Journal of Neurochemistry Oct 2016Alterations of the cerebrospinal fluid (CSF) composition are useful clinical diagnostic tools as well as a source of candidates for new biomarkers of neurodegenerative...
Alterations of the cerebrospinal fluid (CSF) composition are useful clinical diagnostic tools as well as a source of candidates for new biomarkers of neurodegenerative disorders. This Editorial highlights a study by Rodrigues and colleagues in which the authors try to establish Tau as a new biomarker for Huntington´s disease (HD). The study confirmed in two independent, age-controlled patient populations at various disease stages, asymptomatic mutation carriers and healthy controls, that CSF total Tau concentrations in HD gene mutation carriers are increased compared with healthy controls. This is a strong evidence that CSF total Tau concentration is associated with phenotypic variability in HD. Read the highlighted article 'Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease' on page 22.
Topics: Biomarkers; Humans; Huntington Disease; Predictive Value of Tests; tau Proteins
PubMed: 27651306
DOI: 10.1111/jnc.13762 -
Neuroscience Bulletin Nov 2022Huntington's disease (HD) is an autosomal dominantly-inherited neurodegenerative disease, which is caused by CAG trinucleotide expansion in exon 1 of the Huntingtin... (Review)
Review
Huntington's disease (HD) is an autosomal dominantly-inherited neurodegenerative disease, which is caused by CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. Although HD is a rare disease, its monogenic nature makes it an ideal model in which to understand pathogenic mechanisms and to develop therapeutic strategies for neurodegenerative diseases. Clustered regularly-interspaced short palindromic repeats (CRISPR) is the latest technology for genome editing. Being simple to use and highly efficient, CRISPR-based genome-editing tools are rapidly gaining popularity in biomedical research and opening up new avenues for disease treatment. Here, we review the development of CRISPR-based genome-editing tools and their applications in HD research to offer a translational perspective on advancing the genome-editing technology to HD treatment.
Topics: Humans; Gene Editing; Huntington Disease; CRISPR-Cas Systems; Neurodegenerative Diseases
PubMed: 35608753
DOI: 10.1007/s12264-022-00880-3 -
Biochimica Et Biophysica Acta May 2012Huntington's disease (HD) is a prototypical neurodegenerative disease in which there is selective neuronal degeneration, which leads to progressive disability,... (Review)
Review
Huntington's disease (HD) is a prototypical neurodegenerative disease in which there is selective neuronal degeneration, which leads to progressive disability, manifesting itself as a movement disorder, with both psychiatric and cognitive impairment. The disease is caused by a cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin gene, which causes an expanded polyglutamine repeat in the huntingtin protein, resulting in a protein with a novel gain of function. The mutant huntingtin protein causes neuronal dysfunction and eventual cell death in which transcriptional impairment, excitotoxicity, oxidative damage, inflammation, apoptosis and mitochondrial dysfunction are all implicated. A critical transcriptional impairment may be impaired expression and function of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), a master co-regulator of mitochondrial biogenesis and expression of antioxidant enzymes. A deficiency of PGC-1α leads to increased vulnerability to oxidative stress and to striatal degeneration. The extent and severity of the oxidative damage in HD are features well recognized but perhaps under-appreciated. Oxidative damage occurs to lipids, proteins and deoxyribonucleic acid (DNA), and it has been suggested that the latter may contribute to CAG repeat expansion during DNA repair [1]. A marked elevation of oxidized DNA bases occurs in patients' plasma, which may provide a biomarker of disease progression. Antioxidants are effective in slowing disease progression in transgenic mouse models of HD, and show promise in human clinical trials. Strategies to transcriptionally increase expression of antioxidant enzymes by modulating the Nrf-2/ARE pathway, or by increasing expression of PGC-1α hold great promise for developing new treatments to slow or halt the progression of HD. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
Topics: Antioxidants; Humans; Huntington Disease; Oxidative Stress; Reactive Oxygen Species
PubMed: 22138129
DOI: 10.1016/j.bbadis.2011.11.014 -
Journal of Huntington's Disease 2020The current dogma of HD pathoetiology posits it is a degenerative disease affecting primarily the striatum, caused by a gain of function (toxicity) of the mutant mHTT... (Review)
Review
The current dogma of HD pathoetiology posits it is a degenerative disease affecting primarily the striatum, caused by a gain of function (toxicity) of the mutant mHTT that kills neurons. However, a growing body of evidence supports an alternative theory in which loss of function may also influence the pathology.This theory is predicated on the notion that HTT is known to be a vital gene for brain development. mHTT is expressed throughout life and could conceivably have deleterious effects on brain development. The end event in the disease is, of course, neurodegeneration; however the process by which that occurs may be rooted in the pathophysiology of aberrant development.To date, there have been multiple studies evaluating molecular and cellular mechanisms of abnormal development in HD, as well as studies investigating abnormal brain development in HD animal models. However, direct study of how mHTT could affect neurodevelopment in humans has not been approached until recent years. The current review will focus on the most recent findings of a unique study of children at-risk for HD, the Kids-HD study. This study evaluates brain structure and function in children ages 6-18 years old who are at risk for HD (have a parent or grand-parent with HD).
Topics: Adolescent; Brain; Child; Genetic Predisposition to Disease; Humans; Huntingtin Protein; Huntington Disease; Intelligence; Neurodevelopmental Disorders
PubMed: 32925079
DOI: 10.3233/JHD-200394 -
Journal of Huntington's Disease 2019Glycation is the non-enzymatic reaction between reactive dicarbonyls and amino groups, and gives rise to a variety of different reaction products known as advanced... (Review)
Review
Glycation is the non-enzymatic reaction between reactive dicarbonyls and amino groups, and gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). Accumulation of AGEs on proteins is inevitable, and is associated with the aging process. Importantly, glycation is highly relevant in diabetic patients that experience periods of hyperglycemia. AGEs also play an important role in neurodegenerative diseases including Alzheimer's (AD) and Parkinson's disease (PD). Huntington's disease (HD) is a hereditary neurodegenerative disease caused by an expansion of a CAG repeat in the huntingtin gene. The resulting expanded polyglutamine stretch in the huntingtin (HTT) protein induces its misfolding and aggregation, leading to neuronal dysfunction and death. HD patients exhibit chorea and psychiatric disturbances, along with abnormalities in glucose and energy homeostasis. Interestingly, an increased prevalence of diabetes mellitus has been reported in HD and in other CAG triplet repeat disorders. However, the mechanisms underlying the connection between glycation and HD progression remain unclear. In this review, we explore the possible connection between glycation and proteostasis imbalances in HD, and posit that it may contribute to disease progression, possibly by accelerating protein aggregation and deposition. Finally, we review therapeutic interventions that might be able to alleviate the negative impact of glycation in HD.
Topics: Animals; Brain; Glycation End Products, Advanced; Humans; Huntington Disease; Neurons
PubMed: 31322580
DOI: 10.3233/JHD-190366 -
International Journal of Molecular... Mar 2023Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and... (Review)
Review
Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin () protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades.
Topics: Humans; Huntington Disease; Leukocytes, Mononuclear; Cognition Disorders; Biomarkers; Cognitive Dysfunction; Huntingtin Protein
PubMed: 37047023
DOI: 10.3390/ijms24076051 -
International Journal of Molecular... May 2022Huntington's disease (HD) is a devastating neurodegenerative disorder that is caused by an abnormal expansion of CAG repeats in the Huntingtin () gene. Although the main... (Review)
Review
Huntington's disease (HD) is a devastating neurodegenerative disorder that is caused by an abnormal expansion of CAG repeats in the Huntingtin () gene. Although the main symptomatology is explained by alterations at the level of the central nervous system, predominantly affecting the basal ganglia, a peripheral component of the disease is being increasingly acknowledged. Therefore, the manifestation of the disease is complex and variable among CAG expansion carriers, introducing uncertainty in the appearance of specific signs, age of onset and severity of disease. The monogenic nature of the disorder allows a precise diagnosis, but the use of biomarkers with prognostic value is still needed to achieve clinical management of the patients in an individual manner. In addition, we need tools to evaluate the patient's response to potential therapeutic approaches. In this review, we provide a succinct summary of the most interesting molecular biomarkers that have been assessed in patients, mostly obtained from body fluids such as cerebrospinal fluid, peripheral blood and saliva.
Topics: Biomarkers; Heterozygote; Humans; Huntingtin Protein; Huntington Disease; Neurodegenerative Diseases
PubMed: 35628221
DOI: 10.3390/ijms23105411