scholarly journals Therapeutics Advancement for Huntington Disease

2019 ◽  
Author(s):  
Ashok Kumar ◽  
Vijay Kumar ◽  
Kritanjali Singh ◽  
You-Sam Kim ◽  
Yun-Mi Lee ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Review Literature ◽  
Cag Repeats ◽  
Mutant Huntingtin ◽  
Transcriptional Dysregulation ◽  
Psychiatric Disturbances ◽  
Mutant Huntingtin Protein ◽  
Exon 1 ◽  
Disease Modifying ◽  
Novel Therapeutic Strategies

Huntington disease (HD) is an autosomal dominantly inherited fatal neurodegenerative disease. It affects motor, cognitive and psychiatric functions, and ultimately leads to death. The pathology of the disease is due to an expansion of CAG repeats in exon 1 of the huntingtin gene on chromosome 4, which produces a mutant huntingtin protein (mhtt). HD patients manifest a typical phenotype of sporadic, rapid, involuntary control of limb movement, stiffness of limbs, impaired cognition and severe psychiatric disturbances. A variety of symptomatic treatments (which target excitotoxicity, the dopamine pathway, caspases, aggregation, mitochondrial dysfunction, transcriptional dysregulation, mHtt, nucleic acid, neurodegeneration, fetal neural transplants, etc.) are currently available, and new symptomatic and potentially disease-modifying therapies are being actively developed. Recent advances in novel therapeutic strategies, including targeting mutant huntingtin (mhtt) and the htt gene, promise another wave of disease-modifying trials in the near future. A better appreciation of heterogeneous clinical phenomenology and immediate tractable treatment goals coupled with advances in new therapeutics heralds a golden age of HD treatment that will positively impact the quality of life and longevity of HD patients and inform advances in other inherited and neurodegenerative neurological disorders. In the present review literature, our aims to address the latest research on promising therapeutics based on influencing the hypothesized pathological mechanisms associated with HD.

scholarly journals A Case of Previously Unsuspected Huntington Disease Diagnosed at Autopsy

2017 ◽  
Vol 7 (1) ◽  
pp. 136-144
Author(s):  
Catherine R. Miller ◽  
Nobby C. Mambo ◽  
Jianli Dong ◽  
Gerald A. Campbell
Keyword(s):  
Genetic Testing ◽  
Huntington Disease ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Case Reports ◽  
Neuronal Loss ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Psychiatric Disturbances ◽  
Personality Changes

Huntington disease (HD) is a neurodegenerative disorder with a worldwide prevalence of four to ten per 100 000. It is characterized by choreiform movements, behavioral/psychiatric disturbances, and eventual cognitive decline. Symptoms usually present between 30 and 50 years of age and the diagnosis is based on the combination of clinical symptoms, family history, and genetic testing. A variation of HD, juvenile Huntington disease (JHD), presents earlier, with more severe symptoms and with a worse prognosis. Symptoms are different in JHD, with personality changes and learning difficulties being the predominant presenting features. Seizures are common in JHD, and chorea is uncommon; movement disorders at presentation of JHD are predominantly nonchoreiform. The inheritance pattern for both HD and JHD is autosomal dominant and the disease is caused by an elongation of the CAG repeat in the huntingtin gene. There are many published case reports of Huntington disease that were confirmed at autopsy, but to our knowledge, there are no reports in the literature where the diagnosis of Huntington disease was first made at autopsy. We present a case of a 28-year-old African-American male who was in a state of neglect due to a lifetime of abuse, cognitive difficulties, and seizures, whose cause of death was pneumonia. The gross autopsy findings included bilateral caudate nucleus atrophy and lateral ventricular dilation. Microscopically, severe bilateral neuronal loss and gliosis of the caudate and putamen nuclei were seen. Genetic testing for the number of CAG repeats confirmed the diagnosis and was consistent with JHD.

scholarly journals α-Synuclein overexpression promotes aggregation of mutant huntingtin

2000 ◽  
Vol 346 (3) ◽  
pp. 577-581 ◽  
Author(s):  
Robert A. FURLONG ◽  
Yolanda NARAIN ◽  
Julia RANKIN ◽  
Andreas WYTTENBACH ◽  
David C. RUBINSZTEIN
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Enhanced Green Fluorescent Protein ◽  
Fluorescent Protein ◽  
Cag Repeats ◽  
Mutant Huntingtin ◽  
Inclusion Formation ◽  
Exon 1 ◽  
Green Fluorescent

Protein aggregates are a neuropathological feature of Huntington's disease and Parkinson's disease. Mutant huntingtin exon 1 with 72 CAG repeats fused to enhanced green fluorescent protein (EGFP) forms hyperfluorescent inclusions in PC12 cells. Inclusion formation is enhanced in cells co-transfected with EGFP-huntingtin-(CAG)72 and α-synuclein, a major component of Parkinson's disease aggregates. However, α-synuclein does not form aggregates by itself, nor does it appear in huntingtin inclusions in vitro.

scholarly journals Nucleolar stress controls mutant Huntingtin toxicity and monitors Huntington disease progression

2021 ◽  
Author(s):  
Aynur Soenmez ◽  
Rasem Mustafa ◽  
Salome T Ryll ◽  
Francesca Tuorto ◽  
Ludivine Wacheul ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Model ◽  
Huntington Disease ◽  
Neurodegenerative Disorder ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Cag Repeats ◽  
Mutant Huntingtin ◽  
The Impact

Transcriptional and cellular stress surveillance deficits are hallmarks of Huntington disease (HD), a fatal autosomal dominant neurodegenerative disorder, caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD remain unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo is elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases mHTT disperse state in the nucleus, exacerbating the motor deficits. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its nucleolar localization. NPM1 de-localization occurs in the striatum and in the skeletal muscle of the progressive zQ175 knock-in HD mouse model, mimicking the phenotype of HD patients in skeletal muscle biopsies. Taken together, we showed that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identified NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

scholarly journals Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Andrea Gallardo-Orihuela ◽  
Irati Hervás-Corpión ◽  
Carmen Hierro-Bujalance ◽  
Daniel Sanchez-Sotano ◽  
Gema Jiménez-Gómez ◽  
...  
Keyword(s):  
Mouse Models ◽  
Neuronal Development ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Cag Repeats ◽  
Brain Areas ◽  
Transcriptional Dysregulation ◽  
Transcriptional Alterations ◽  
Exon 1 ◽  
The Brain

AbstractHuntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative correlation between the number of CAG repeats and the age of disease onset is established, additional factors may contribute to the high heterogeneity of the complex manifestation of symptoms among patients. This variability is also observed in mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analysed the R6/1 strain in search of potential correlates between pathological motor/cognitive phenotypical traits and transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated across the examined brain areas (the prefrontal cortex, striatum, hippocampus and cerebellum), exhibited tissue-specific correlations with particular phenotypical traits that were attributable to the contribution of the brain region to that trait (e.g., striatum and rotarod performance, cerebellum and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation associated with HD was partially exacerbated in mice that showed poor overall phenotypical scores, especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relatively better outcomes, such as Nfya (CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development, apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to the highly heterogeneous population of HD patients.

scholarly journals Therapeutic Advances for Huntington’s Disease

2020 ◽  
Vol 10 (1) ◽  
pp. 43 ◽  
Author(s):  
Ashok Kumar ◽  
Vijay Kumar ◽  
Kritanjali Singh ◽  
Sukesh Kumar ◽  
You-Sam Kim ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Involuntary Movement ◽  
Cag Repeats ◽  
Transcriptional Dysregulation ◽  
Psychiatric Disturbances ◽  
Personality Changes ◽  
New Gene ◽  
Therapeutic Research ◽  
Analytical Tools

Huntington’s disease (HD) is a progressive neurological disease that is inherited in an autosomal fashion. The cause of disease pathology is an expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin gene (HTT) on chromosome 4 (4p16.3), which codes the huntingtin protein (mHTT). The common symptoms of HD include motor and cognitive impairment of psychiatric functions. Patients exhibit a representative phenotype of involuntary movement (chorea) of limbs, impaired cognition, and severe psychiatric disturbances (mood swings, depression, and personality changes). A variety of symptomatic treatments (which target glutamate and dopamine pathways, caspases, inhibition of aggregation, mitochondrial dysfunction, transcriptional dysregulation, and fetal neural transplants, etc.) are available and some are in the pipeline. Advancement in novel therapeutic approaches include targeting the mutant huntingtin (mHTT) protein and the HTT gene. New gene editing techniques will reduce the CAG repeats. More appropriate and readily tractable treatment goals, coupled with advances in analytical tools will help to assess the clinical outcomes of HD treatments. This will not only improve the quality of life and life span of HD patients, but it will also provide a beneficial role in other inherited and neurological disorders. In this review, we aim to discuss current therapeutic research approaches and their possible uses for HD.

Huntington’s Disease and Mitochondrial DNA Deletions: Event or Regular Mechanism for Mutant Huntingtin Protein and CAG Repeats Expansion?!

2007 ◽  
Vol 27 (7) ◽  
pp. 867-875 ◽  
Author(s):  
Mohammad Mehdi Banoei ◽  
Massoud Houshmand ◽  
Mehdi Shafa Shariat Panahi ◽  
Parvin Shariati ◽  
Maryam Rostami ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeats ◽  
Mutant Huntingtin ◽  
Huntingtin Protein ◽  
Dna Deletions ◽  
Mutant Huntingtin Protein

scholarly journals Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Koning Shen ◽  
Barbara Calamini ◽  
Jonathan A Fauerbach ◽  
Boxue Ma ◽  
Sarah H Shahmoradian ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Brain Slices ◽  
Mutant Huntingtin ◽  
Rich Domain ◽  
Mutant Huntingtin Protein ◽  
Exon 1 ◽  
Opposing Effects ◽  
Polyq Tract ◽  
Polyq Expansion

Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington’s disease (HD), neurotoxicity correlates with an increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation. However, in neurons both domains act synergistically to engage protective chaperone and degradation pathways promoting mHtt proteostasis. Surprisingly, when proteotoxicity was assessed in rat corticostriatal brain slices, either flanking region alone sufficed to generate a neurotoxic conformation, while the polyQ tract alone exhibited minimal toxicity. Linking mHtt structural properties to its neuronal proteostasis should inform new strategies for neuroprotection in polyQ-expansion diseases.

scholarly journals Proteolysis of Mutant Huntingtin Produces an Exon 1 Fragment That Accumulates as an Aggregated Protein in Neuronal Nuclei in Huntington Disease

2010 ◽  
Vol 285 (12) ◽  
pp. 8808-8823 ◽  
Author(s):  
Christian Landles ◽  
Kirupa Sathasivam ◽  
Andreas Weiss ◽  
Ben Woodman ◽  
Hilary Moffitt ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Mutant Huntingtin ◽  
Neuronal Nuclei ◽  
Exon 1

scholarly journals Nascent mutant Huntingtin exon 1 chains do not stall on ribosomes during translation but aggregates do recruit machinery involved in ribosome quality control

2020 ◽  
Author(s):  
Angelique R. Ormsby ◽  
Dezerae Cox ◽  
James Daly ◽  
David Priest ◽  
Elizabeth Hinde ◽  
...  
Keyword(s):  
Cell Culture ◽  
Quality Control ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Amyloid Formation ◽  
Mutant Huntingtin ◽  
Translational Machinery ◽  
Nascent Chain ◽  
Mutant Huntingtin Protein ◽  
Exon 1

AbstractMutations that cause Huntington’s Disease involve a polyglutamine (polyQ) sequence expansion beyond 35 repeats in exon 1 of Huntingtin. Intracellular inclusion bodies of mutant Huntingtin protein are a key feature of Huntington’s disease brain pathology. We previously showed that in cell culture the formation of inclusions involved the assembly of disordered structures of mHtt exon 1 fragments (Httex1) and they were enriched with translational machinery when first formed. We hypothesized that nascent mutant Httex1 chains co-aggregate during translation by phase separation into liquid-like disordered aggregates and then convert to more rigid, amyloid structures. Here we further examined the mechanisms of inclusion assembly in a human epithelial kidney (AD293) cell culture model and examined whether ribosome quality control machinery previously implicated in stalled ribosomes were involved. We found mHttex1 did not appear to stall translation of its own nascent chain and there was no recruitment of RNA into inclusions. However, proteins involved in translation or ribosome quality control were co-recruited into the inclusions (Ltn1 and Rack1) compared to a protein not anticipated to be involved (NACAD). Furthermore, we observed co-aggregation with other proteins previously identified in inclusions, including Upf-1 and chaperone-like proteins Sgta and Hspb1, which also suppressed aggregation at high co-expression levels. The newly formed inclusions contained immobile mHttex1 molecules which points to the disordered aggregates being mechanically rigid prior to amyloid formation.

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