• METHODS We cotransfected neuronal (SK-N-SH, human neuroblastoma) and non-neuronal (COS-7, monkey kidney) cell lines with HD exon 1 (containing either 21 or 72 CAG repeats) construct DNA and either full length wild type huntingtin or pFLAG (control vector). (bmj.com)
  • RESULTS Full length wild type huntingtin significantly reduced cell death resulting from the mutant HD exon 1 fragments containing 72 CAG repeats in both cell lines. (bmj.com)
  • Wild type huntingtin did not significantly modulate cell death caused by transfection of HD exon 1 fragments containing 21 CAG repeats in either cell line. (bmj.com)
  • CONCLUSIONS Our results suggest that wild type huntingtin can significantly reduce the cellular toxicity of mutant HD exon 1 fragments in both neuronal and non-neuronal cell lines. (bmj.com)
  • 35) in the first exon of the huntingtin ( HTT , IT15 ) gene 1 . (nature.com)
  • Exon 1 contains a CAG trinucleotide repeat that encodes the amino acid glutamine, followed by another repeat that encodes proline. (jci.org)
  • At the molecular level, HD occurs due to an increase in the number of CAG repeats in the first exon of the gene encoding the huntingtin protein. (frontiersin.org)
  • Huntington disease (HD) is an inherited neurodegenerative disorder characterized by motor and cognitive dysfunction caused by expansion of polyglutamine (polyQ) repeat in exon 1 of huntingtin (HTT). (en-journal.org)
  • The cause of this fatal disease is an aberrant expansion of CAG trinucleotide in the exon 1 of HTT gene, translating into a polyglutamine tract (polyQ) at the N-terminus, and conferring gain-of-function and loss-of-function to wild type huntingtin protein. (biomedcentral.com)
  • Huntington's disease (HD) is the most prevalent autosomal dominant, trinucleotide repeat neurodegenerative disease. (grantome.com)
  • Huntington's disease (HD) is an autosomal dominant neurodegenerative condition associated with abnormal movements, cognitive deterioration, and psychiatric symptoms. (bmj.com)
  • Huntington's disease (HD) is a severe autosomal-dominant neurodegenerative disorder caused by a mutation within a gene, encoding huntingtin protein. (frontiersin.org)
  • Huntington disease (HD) is a rare, autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG repeat sequence in the Huntingtin ( HTT ) gene. (biomedcentral.com)
  • Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded CAG repeat (greater than 38) on the short arm of chromosome 4, resulting in loss and dysfunction of neurons in the neostriatum and cortex, leading to cognitive decline, motor dysfunction, and death, typically occurring 15 to 20 years after the onset of motor symptoms. (biomedcentral.com)
  • Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded and unstable CAG trinucleotide repeat that results in a progressive degeneration of neurons, primarily in the putamen, caudate nucleus, and cerebral cortex. (biomedcentral.com)
  • Expansion of CAG repeats of cytosine-adenine-guanine (known as a trinucleotide repeat expansion) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mHtt), which gradually damages brain cells through a number of possible mechanisms. (wikipedia.org)
  • It is caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin ( HTT ) gene on chromosome 4, which is responsible for the expression of the protein huntingtin ( Nance, 2017 ). (frontiersin.org)
  • Huntington's disease (HD) is caused by expansion of polyglutamine repeats in the protein huntingtin, which affects the corpus striatum of the brain. (encyclopedia.pub)
  • HD is typically inherited from an affected parent, who carries a mutation in the huntingtin gene (HTT). (wikipedia.org)
  • The mutation leads to the abnormal expansion of the production of the polyglutamine tract (polyQ) resulting in the form of an unstable Huntingtin protein commonly referred to as mutant Huntingtin. (benthamscience.com)
  • Mutant Huntingtin is the cause of the complex neurological metabolic alteration of Huntington's disease, resulting in both the loss of all the functions of normal Huntingtin and the genesis of abnormal interactions due to the presence of this mutation. (benthamscience.com)
  • The huntingtin gene encodes a protein of 350 kD;the disease causing mutation is an expansion of an amino-terminal polyglutamine repeat of more than 36 successive glutamines. (grantome.com)
  • The causative mutation is a (CAG) n trinucleotide repeat expansion of more than 35 repeats, which is translated into an abnormally long polyglutamine tract in the huntingtin protein. (bmj.com)
  • 2 The polyglutamine expansion mutation causes disease by conferring a novel deleterious function on the mutant protein and the severity correlates with increasing CAG repeat number and expression levels in transgenic mice and in cell culture models. (bmj.com)
  • While the experiments in the current paper were in progress, Leavitt et al 7 provided in vivo evidence suggesting that wild type huntingtin can protect against the gain of function mutation caused by the expanded polyglutamine tract in mutant huntingtin, using a YAC transgenic mouse model. (bmj.com)
  • OBJECTIVES Recent data suggest that wild type huntingtin can protect against apoptosis in the testis of mice expressing full length huntingtin transgenes with expanded CAG repeats. (bmj.com)
  • Western blot analysis of HD brain tissue shows full-length huntingtin protein in the nuclear fraction as well as abundant immunopositive bands at lower molecular weight, suggesting proteolytic products in the nucleus. (jci.org)
  • However, comparing the HD76 neurons with the previously described low-repeat HD models, we have demonstrated that the severity of calcium signaling alterations does not depend on the length of the polyglutamine tract of the mutant huntingtin. (frontiersin.org)
  • The aberrant polyQ tract results in Huntingtin protein misfolding, which generates insoluble intracellular inclusions and aggregates, important hallmarks of the disease. (biomedcentral.com)
  • Transcriptional dysregulation is one of the main cellular processes affected by mutant Huntingtin (mHtt). (bvsalud.org)
  • Mutant huntingtin (mHtt) aggregates and affects cellular processes in multiple ways [ 2 ] . (encyclopedia.pub)
  • The aggregates are ubiquitinated, although antibodies against huntingtin appear to stain more aggregates than do antibodies against ubiquitin. (jci.org)
  • Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. (nature.com)
  • Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the Huntingtin gene. (bvsalud.org)
  • In all cases, age at onset correlates inversely with repeat number. (bmj.com)
  • In order to identify genes that may modify disease onset and progression, genome-wide association and gene expression studies have been performed 12 , 13 . (nature.com)
  • Human genome-wide association studies have identified FAN1 and several DNA mismatch repair (MMR) genes as modifiers of Huntington's disease age of onset. (bvsalud.org)
  • These results provide a mechanistic basis for the role of FAN1 in preventing repeat expansion and could explain the antagonistic effects of MMR and FAN1 in disease onset/progression. (bvsalud.org)
  • The age of onset of the disease varies inversely with the number of CAG repeats. (jci.org)
  • Individuals with juvenile onset usually have over 55 repeats, and they usually inherit the gene from their father. (jci.org)
  • Huntington's disease is a genetic neurological disorder caused by a repeated expansion of the CAG trinucleotide, causing instability in the N-terminal of the gene coding for the Huntingtin protein. (benthamscience.com)
  • Aim 2 investigates in post-mortem HD brain post- transcriptional regulation of huntingtin mRNA, to find molecular processes that favor synthesis of mutant huntingtin mRNA. (grantome.com)
  • Co-transcriptional formation of stable RNA·DNA hybrids can also enhance the instability of repeat tracts. (bvsalud.org)
  • Transcriptional dysregulation is considered a key molecular mechanism responsible of HD pathogenesis but, although numerous studies investigated mRNA alterations in HD, so far none evaluated a whole gene expression profile in blood of R6/2 mouse model. (biomedcentral.com)
  • In animal models, FAN1 prevents somatic expansion of CAG triplet repeats, whereas MMR proteins promote this process. (bvsalud.org)
  • proteinopathic adj ), or proteopathy , protein conformational disorder , or protein misfolding disease , is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells , tissues and organs of the body. (wikipedia.org)
  • For example, cystic fibrosis is caused by a defective cystic fibrosis transmembrane conductance regulator (CFTR) protein, [3] and in amyotrophic lateral sclerosis / frontotemporal lobar degeneration (FTLD), certain gene-regulating proteins inappropriately aggregate in the cytoplasm, and thus are unable to perform their normal tasks within the nucleus. (wikipedia.org)
  • For example, proteins that are normally unfolded or relatively unstable as monomers (that is, as single, unbound protein molecules) are more likely to misfold into an abnormal conformation. (wikipedia.org)
  • The abnormal aggregation and accumulation of specific proteins in the form of cytoplasmic inclusion is common pathological feature of most age-related neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD) and amyotrophic lateral sclerosis (ALS). (en-journal.org)
  • Huntington disease (HD) is associated with an excessive sequence of CAG repeats in the 5' end of HTT (alias IT15- interesting transcript number 15), a 350-kD gene located on the short arm of chromosome 4. (medscape.com)
  • The huntingtin gene provides the genetic information for huntingtin protein (Htt). (wikipedia.org)
  • Genetic testing revealed 43 CAG repeats in the HD gene. (medscape.com)
  • One of the problems arising from the misfolded Huntingtin is the increase in oxidative stress, which is common in many neurological diseases such as Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis and Creutzfeldt-Jakob disease. (benthamscience.com)
  • The activation of this pathway modulates gene transcription and activates multiple downstream Kinasesphosphatases branches, affecting key cellular processes such as protein synthesis, autophagy, apoptosis, and resistance to oxidative stress [ 9 ]. (scientificarchives.com)
  • The underlying pathology of HD is initiated when the gene that codes for the huntingtin (htt) protein, located on the short arm of chromosome 4, contains an increased number of CAG repeats [ 1 ]. (biomedcentral.com)
  • Expansion of polyQ increases the propensity for HTT protein aggregation, process known to be implicated in neurodegeneration. (en-journal.org)
  • Huntington Disease (HD) is a hereditary neurological disorder that shows a gene expansion associated with trinucleotide repeats. (medicalalgorithms.com)
  • Huntington Disease (HD) is a progressive neurological disorder, with pathological manifestations in brain areas and in periphery caused by the ubiquitous expression of mutant Huntingtin protein. (biomedcentral.com)
  • Thus demonstrated, our core idea is that RNA silencing is useful to selectively reduce mutant huntingtin expression and slow or block neuronal dysfunction and death in HD. (grantome.com)
  • We hypothesize that selective knockdown of mutant huntingtin restores normal neuronal function, but excessive silencing impairs neuronal function by interfering with essential signaling events. (grantome.com)
  • Aim 3 studies cellular mechanisms by which RNAi restores essential neuronal signaling activity in HD cells and the threshold for wild type huntingtin to main normal neuronal integrity. (grantome.com)
  • The clear appearance of symptoms such as rigidity, writhing motions, or abnormal posturing appear as the disorder progresses. (wikipedia.org)
  • In fact, we know that in people with other diseases that involve the striatum such as Parkinson's disease, these symptoms are related to abnormal reward signals in the striatum. (hdsa.org)
  • In this study, mesenchymal stem cells isolated from the bone-marrow of mice (BM MSCs), were labeled with Hoechst after low (3 to 8) or high (40 to 50) numbers of passages and then transplanted intrastriatally into 5-week-old R6/2 mice, which carries the N-terminal fragment of the human HD gene (145 to 155 repeats) and rapidly develops symptoms analogous to the human form of the disease. (biomedcentral.com)
  • This suggests that wild type huntingtin can be protective in different cell types and that it can act against the toxicity caused by a mutant huntingtin fragment as well as against a full length transgene. (bmj.com)
  • We were interested to test if wild type huntingtin protected against the toxicity of polyglutamine expansion mutations. (bmj.com)
  • The polyglutamine repeats in mutant huntingtin cause its aggregation and elicit toxicity by affecting several cellular processes, which include dysregulated organellar stress responses. (encyclopedia.pub)
  • It is not clear if this protective effect was confined to particular cell types, or if wild type huntingtin exerted its protective effect in this model by simply reducing the formation of toxic proteolytic fragments from mutant huntingtin. (bmj.com)
  • The large number of genes and the diversity of processes involved in the progression of neurological diseases in general, and HD in specific, emphasizes the need for comprehensive approaches in additional to studies of individual genes 14 . (nature.com)
  • We will examine how gene silencing can reduce production of the mutant huntingtin protein that causes HD, thereby preventing dysfunction and death in neurons in animal models of HD and in HD neurons in culture. (grantome.com)
  • HD supposedly can cause psychiatric disorders in 2 ways: (1) by the direct action of the gene on striatal neurons, and (2) by the indirect effect of the disordered family environment on the children, regardless of whether they inherited the HD gene. (medscape.com)
  • Here we have also observed greater expression of huntingtin and an activator of store-operated calcium channels STIM2 in HD76 neurons. (frontiersin.org)
  • It allows users to obtain, visualize and prioritize molecular interaction networks using HD-relevant gene expression, phenotypic and other types of data obtained from human samples or model organisms. (nature.com)
  • To understand the molecular basis of these opposing effects, we evaluated FAN1 nuclease function on DNA extrahelical extrusions that represent key intermediates in triplet repeat expansion. (bvsalud.org)
  • The R6/2 mouse model of HD expresses the N-terminal portion of human htt, containing a highly expanded glutamine repeat (145 to 155). (biomedcentral.com)
  • We will identify abnormal eye-movements that may indicate the presence and severity of HD. (hdsa.org)
  • Activation of FAN1 in this manner results in DNA cleavage in the vicinity of triplet repeat extrahelical extrusions thereby leading to their removal in human cell extracts. (bvsalud.org)
  • it results from expansion of polyglutamine repeats in the protein huntingtin [ 1 ] . (encyclopedia.pub)
  • We showed previously that cytoplasmic release of mtDNA activates the cGAS STING TBK1 pathway resulting in interferon-stimulated gene (ISG) expression that promotes antiviral immunity4. (regenerativemedicine.net)
  • Here, we find that persistent mtDNA stress is not associated with basally activated NF-κB signalling or interferon gene expression typical of an acute antiviral response. (regenerativemedicine.net)
  • In unaffected individuals, there are 10-34 CAG repeats. (jci.org)
  • 2] Healthy individuals may have between 9 and 35 CAG repeats, while patients diagnosed with HD, as well as carriers, have an abnormal expansion accommodating 36 or more CAG repeats. (medscape.com)
  • This proposal addresses treatment of HD through study of basic mechanisms of silencing the gene that causes the disease. (grantome.com)
  • Selected genes derived from these pathways were additionally investigated in other accessible tissues to validate these matrices as source of biomarkers, and in brain, to link central and peripheral disease manifestations. (biomedcentral.com)
  • An expansion of 36 or more CAGs can lead to the disease, with earlier onsets associated with longer CAG repeats. (biomedcentral.com)
  • Huntingtin is expressed in the cytoplasm of most cells in the body. (jci.org)
  • Myotonic dystrophy type 1 is the most frequent form of muscular dystrophy in adults caused by an abnormal expansion of the CTG trinucleotide. (bvsalud.org)
  • Aim 1 examines in vivo in mice whether allele specific silencing can delay or prevent HD neuropathy and abnormal behaviors. (grantome.com)
  • Possibly, the abnormal huntingtin protein undergoes proteolysis and is then transported to the nucleus, where it undergoes aggregation. (medscape.com)
  • Innovations include targeting mRNA alleles for RNAi, use of HD mouse models that express only human huntingtin genes, quantitative measurement of huntingtin allelic mRNA based on SNP heterozygosities, deep sequencing analysis to identify 3 UTR huntingtin mRNA regulation, and zinc finger nuclease strategy to eliminate huntingtin alleles at the genomic level. (grantome.com)
  • This proposal satisfies NINDS goals in translational science: translation of gene silencing therapeutics, early-state therapy development, and identifying mechanisms that underlie nervous system function. (grantome.com)
  • The function of wild type huntingtin is unclear. (bmj.com)
  • Huntingtin contains a few domains that suggest particular functions, including WW domains and caspase cleavage sites ( 7 , 8 ), but the function of the protein remains unknown. (jci.org)
  • Ophthalmologic findings of AD include visual field deficits, decreased contrast sensitivity, impaired oculomotor function, and abnormal viewing behavior. (aao.org)
  • However, Rigamonti et al 6 recently showed that wild type huntingtin can protect CNS cells from a variety of apoptotic stimuli, including serum withdrawal, stimulation of death receptors, and pro-apoptotic Bcl-2 homologues. (bmj.com)
  • Moreover, a previously described potential anti-HD drug EVP4593 has been found to attenuate high levels of both huntingtin and STIM2 that may contribute to its neuroprotective effect. (frontiersin.org)