Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008489 (chorea)
 2,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prospective increase in life expectancy will be accompanied by a rise in the number of elderly people who suffer from ill health caused by old age. Many diseases caused by aging are protein misfolding diseases. The molecular mechanisms underlying these disorders receive constant scientific interest. In addition to old age, mutations also cause congenital protein misfolding disorders. Chorea Huntington, one of the most well-known examples, is caused by triplet extensions that can lead to more than 100 glutamines in the N-terminal region of huntingtin, accompanied by huntingtin aggregation. So far, nine disease-associated triplet extensions have also been described for alanine codons. The extensions lead primarily to skeletal malformations. Eight of these proteins represent transcription factors, while the nuclear poly-adenylate binding protein 1, PABPN1, is an RNA binding protein. Additional alanines in PABPN1 lead to the disease oculopharyngeal muscular dystrophy (OPMD). The alanine extension affects the N-terminal domain of the protein, which has been shown to lack tertiary contacts. Biochemical analyses of the N-terminal domain revealed an alanine-dependent fibril formation. However, fibril formation of full-length protein did not recapitulate the findings of the N-terminal domain. Fibril formation of intact PABPN1 was independent of the alanine segment, and the fibrils displayed biochemical properties that were completely different from those of the N-terminal domain. Although intranuclear inclusions have been shown to represent the histochemical hallmark of OPMD, their role in pathogenesis is currently unclear. Several cell culture and animal models have been generated to study the molecular processes involved in OPMD. These studies revealed a number of promising future therapeutic strategies that could one day improve the quality of life for the patients.
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PMID:The unresolved puzzle why alanine extensions cause disease. 2361 54

Huntington's disease (HD) is an autosomal dominant disorder caused by a tandem repeat expansion encoding an expanded tract of glutamines in the huntingtin protein. HD is progressive and manifests as psychiatric symptoms (including depression), cognitive deficits (culminating in dementia), and motor abnormalities (including chorea). Having reached the twentieth anniversary of the discovery of the "genetic stutter" which causes HD, we still lack sophisticated insight into why so many HD patients exhibit affective disorders such as depression at very early stages, prior to overt appearance of motor deficits. In this review, we will focus on depression as the major psychiatric manifestation of HD, discuss potential mechanisms of pathogenesis identified from animal models, and compare depression in HD patients with that of the wider gene-negative population. The discovery of depressive-like behaviors as well as cellular and molecular correlates of depression in transgenic HD mice has added strong support to the hypothesis that the HD mutation adds significantly to the genetic load for depression. A key question is whether HD-associated depression differs from that in the general population. Whilst preclinical studies, clinical data, and treatment responses suggest striking similarities, there are also some apparent differences. We discuss various molecular and cellular mechanisms which may contribute to depression in HD, and whether they may generalize to other depressive disorders. The autosomal dominant nature of HD and the existence of models with excellent construct validity provide a unique opportunity to understand the pathogenesis of depression and associated gene-environment interactions. Thus, understanding the pathogenesis of depression in HD may not only facilitate tailored therapeutic approaches for HD sufferers, but may also translate to the clinical depression which devastates the lives of so many people.
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PMID:A Tale of Two Maladies? Pathogenesis of Depression with and without the Huntington's Disease Gene Mutation. 2384 83

Huntington's disease (HD) is an incurable and fatal hereditary neurodegenerative disorder of mid-life onset characterized by chorea, emotional distress, and progressive cognitive decline. HD is caused by an expansion of CAG repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Recent studies suggest that epigenetic modifications may play a key role in HD pathogenesis. Alterations of the epigenetic "histone code" lead to chromatin remodeling and deregulation of neuronal gene transcription that are prominently linked to HD pathogenesis. Furthermore, specific noncoding RNAs and microRNAs are associated with neuronal damage in HD. In this review, we discuss how DNA methylation, post-translational modifications of histone, and noncoding RNA function are affected and involved in HD pathogenesis. In addition, we summarize the therapeutic effects of histone deacetylase inhibitors and DNA binding drugs on epigenetic modifications and neuropathological sequelae in HD. Our understanding of the role of these epigenetic mechanisms may lead to the identification of novel biological markers and new therapeutic targets to treat HD.
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PMID:Epigenetic mechanisms of neurodegeneration in Huntington's disease. 2400 38

Huntington disease (HD) is an autosomal dominant, adult-onset, progressive neurodegenerative disease characterized by the triad of abnormal movements (typically chorea), cognitive impairment, and psychiatric problems. It is caused by an expanded CAG repeat in the gene encoding the protein huntingtin on chromosome 4 and causes progressive atrophy of the striatum as well as cortical and other extrastriatal structures. Genetic testing has been available since 1993 to confirm diagnosis in affected adults and for presymptomatic testing in at-risk individuals. This review covers HD signs, symptoms, and pathophysiology; current genetic testing issues; and current and future treatment strategies.
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PMID:Clinical neurogenetics: huntington disease. 2417 25

Huntington's disease (HD) is a fatal genetic disorder characterized by triad clinical symptoms of chorea, emotional distress, and cognitive decline. Genetic mutation in HD is identified by an expansion of CAG repeats coding for glutamine (Q) in exon 1 of the huntingtin (htt) gene. The exact mechanism on how mutant htt leads to the selective loss of medium spiny neurons (MSNs) in the striatum is still unknown. Recent studies suggest that nucleolar stress and dysfunction are linked to the pathogenesis of HD. Alterations of the nucleolar activity and integrity contribute to deregulation of ribosomal DNA (rDNA) transcription in HD pathogenesis. Furthermore, epigenetic modifications in the nucleolus are associated with neuronal damage in HD. In this review, we discuss about how post-translational modifications of upstream binding factor (UBF) are affected by histone acetyltransferase and histone methyltransferase and involved in the transcriptional regulation of rDNA in HD. The understanding of epigenetic modulation of UBF-dependent rDNA transcription in the nucleolus may lead to the identification of novel pathological markers and new therapeutic targets to treat HD. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.
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PMID:Nucleolar dysfunction in Huntington's disease. 2418 5

Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease, caused by expansion of the CAG repeat in the huntingtin (HTT) gene and characterized pathologically by the loss of pyramidal neurons in several cortical areas, of striatal medium spiny neurons, and of hypothalamic neurons. Clinically, a distinguishing feature of the disease is uncontrolled involuntary movements (chorea, dyskensias) accompanied by progressive cognitive, motor, and psychiatric impairment. This review focuses on the current state of therapeutic development for the treatment of HD, including the preclinical and clinical development of small molecules and molecular therapies.
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PMID:Therapeutic Strategies for Huntington's Disease. 2427 42

Huntington's disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.
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PMID:A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease. 2450 62

Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by an expanded trinucleotide CAG sequence in huntingtin gene (HTT) on chromosome 4. HD manifests with chorea, cognitive and psychiatric symptoms. Although advances in genetics allow identification of individuals carrying the HD gene, much is still unknown about the mechanisms underlying the development of overt clinical symptoms and the transitional period between premanifestation and manifestation of the disease. HD has no cure and patients rely only in symptomatic treatment. There is an urgent need to identify biomarkers that are able to monitor disease progression and assess the development and efficacy of novel disease modifying drugs. Over the past years, neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have provided important advances in our understanding of HD. MRI provides information about structural and functional organization of the brain, while PET can detect molecular changes in the brain. MRI and PET are able to detect changes in the brains of HD gene carriers years ahead of the manifestation of the disease and have also proved to be powerful in assessing disease progression. However, no single technique has been validated as an optimal biomarker. An integrative multimodal imaging approach, which combines different MRI and PET techniques, could be recommended for monitoring potential neuroprotective and preventive therapies in HD. In this article we review the current neuroimaging literature in HD.
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PMID:Neuroimaging in Huntington's disease. 2497 32

Huntington's disease (HD) is a devastating neurodegenerative disorder that directly affects more than 1 in 10,000 persons in Western societies but, as a family disorder with a long, costly, debilitating course, it has an indirect impact on a far greater proportion of the population. Although some palliative treatments are used, no effective treatment exists for preventing clinical onset of the disorder or for delaying its inevitable progression toward premature death, approximately 15 years after diagnosis. Huntington's disease involves a movement disorder characterized by chorea, as well as a variety of psychiatric disturbances and intellectual decline, with a gradual loss of independence. A dire need exists for effective HD therapies to alleviate the suffering and costs to the individual, family, and health care system. In past decades, genetics, the study of DNA sequence variation and its consequences, provided the tools to map the HD gene to chromosome 4 and ultimately to identify its mutation as an expanded CAG trinucleotide repeat in the coding sequence of a large protein, dubbed huntingtin. Now, advances in genetic technology offer an unbiased route to the identification of genetic factors that are disease-modifying agents in human patients. Such genetic modifiers are expected to highlight processes capable of altering the course of HD and therefore to provide new, human-validated targets for traditional drug development, with the goal of developing rational treatments to delay or prevent onset of HD clinical signs.
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PMID:Genetic modifiers of Huntington's disease. 2515 28

Huntington's disease (HD) is a lethal, autosomal dominant neurodegenerative disorder caused by CAG repeat expansions at exon 1 of the huntingtin (Htt) gene, which encodes for a mutant huntingtin protein (mHtt). Prominent symptoms of HD include motor dysfunction, characterized by chorea; psychiatric disturbances such as mood and personality changes; and cognitive decline that may lead to dementia. Pathologically multiple complex processes and pathways are involved in the development of HD, including selective loss of neurons in the striatum and cortex, dysregulation of cellular autophagy, mitochondrial dysfunction, decreased neurotrophic and growth factor levels, and aberrant regulation of gene expression and epigenetic patterns. No cure for HD presently exists, nor are there drugs that can halt the progression of this devastating disease. Therefore, the need to discover neuroprotective modalities to combat HD is critical. In basic and preclinical studies using cellular and animal HD models, the mood stabilizers lithium and valproic acid (VPA) have shown multiple beneficial effects, including behavioral and motor improvement, enhanced neuroprotection, and lifespan extension. Recent studies in transgenic HD mice support the notion that combined lithium/VPA treatment is more effective than treatment with either drug alone. In humans, several clinical studies of HD patients found that lithium treatment improved mood, and that VPA treatment both stabilized mood and moderately reduced chorea. In contrast, other studies observed that the hallmark features of HD were unaffected by treatment with either lithium or VPA. The current review discusses preclinical and clinical investigations of the beneficial effects of lithium and VPA on HD pathophysiology.
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PMID:Preclinical and clinical investigations of mood stabilizers for Huntington's disease: what have we learned? 2528 35


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