scholarly journals Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Cristine de Paula Nascimento-Castro ◽  
Ana Claudia Wink ◽  
Victor Silva da Fônseca ◽  
Claudia Daniele Bianco ◽  
Elisa C. Winkelmann-Duarte ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Differentiation ◽  
Neurodegenerative Disorder ◽  
Neuropsychiatric Symptoms ◽  
Chronic Administration ◽  
Nuclear Antigen ◽  
Ki 67 ◽  
Affective Symptoms

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide. This study investigated whether chronic administration of the antioxidant probucol improved motor and affective symptoms as well as hippocampal neurogenic function in the YAC128 transgenic mouse model of HD during the early- to mild-symptomatic stages of disease progression. The motor performance and affective symptoms were monitored using well-validated behavioral tests in YAC128 mice and age-matched wild-type littermates at 2, 4, and 6 months of age, after 1, 3, or 5 months of treatment with probucol (30 mg/kg/day via water supplementation, starting on postnatal day 30). Endogenous markers were used to assess the effect of probucol on cell proliferation (Ki-67 and proliferation cell nuclear antigen (PCNA)) and neuronal differentiation (doublecortin (DCX)) in the hippocampal dentate gyrus (DG). Chronic treatment with probucol reduced the occurrence of depressive-like behaviors in early- and mild-symptomatic YAC128 mice. Functional improvements were not accompanied by increased progenitor cell proliferation and neuronal differentiation. Our findings provide evidence that administration of probucol may be of clinical benefit in the management of early- to mild-symptomatic HD.

scholarly journals Exploring the Reliability and Validity of the Huntington’s Disease Quality of Life Battery for Carers (HDQoL-C) within A Polish Population

2019 ◽  
Vol 16 (13) ◽  
pp. 2323
Author(s):  
Bartoszek ◽  
Aubeeluck ◽  
Stupple ◽  
Bartoszek ◽  
Kocka ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Neuropsychiatric Symptoms ◽  
Reliability And Validity ◽  
Polish Population ◽  
Principle Components Analysis ◽  
Wide Range

Huntington’s disease (HD) is a rare genetic neurodegenerative disorder that causes motor disorders, neuropsychiatric symptoms and a progressing deterioration of cognitive functions. Complex issues resulting from the hereditary nature of HD, the complexity of symptoms and the concealed onset of the disease have a great impact on the quality of life of family carers. The caregivers are called the “forgotten people” in HD, especially with relation to genetic counseling. This study aims to explore the reliability and validity of the Huntington’s Disease Quality of Life Battery for carers (HDQoL-C) within a Polish population. A total of 90 carers recruited from the Enroll-HD study in Polish research centers of the European Huntington’s Disease Network completed a polish translation of the HDQoL-C. Data were subjected to Principle Components Analysis (PCA) and reliability measures. The Polish version of the shortened versions of the HDQoL-C is similarly valid compared to the original English version and suitable for use within this population. The HDQoL-C has previously demonstrated a wide range of benefits for practitioners in capturing and understanding carer experience and these benefits can now be extended to Polish speaking populations.

scholarly journals The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease

2021 ◽  
Vol 14 (3) ◽  
pp. 257
Author(s):  
Elisabeth Singer ◽  
Lilit Hunanyan ◽  
Magda M. Melkonyan ◽  
Jonasz J. Weber ◽  
Lusine Danielyan ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cell Model ◽  
Resonance Energy Transfer ◽  
Neuronal Cell ◽  
Resonance Energy ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Cell Models

Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (STHdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT.

scholarly journals RNA Sequencing of Human Peripheral Blood Cells Indicates Upregulation of Immune-Related Genes in Huntington's Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Miguel A. Andrade-Navarro ◽  
Katja Mühlenberg ◽  
Eike J. Spruth ◽  
Nancy Mah ◽  
Adrián González-López ◽  
...  
Keyword(s):  
Gene Expression ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Gene Expression Signature ◽  
Interferon Response ◽  
Peripheral Blood Cells

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a trinucleotide repeat expansion in the Huntingtin gene. As disease-modifying therapies for HD are being developed, peripheral blood cells may be used to indicate disease progression and to monitor treatment response. In order to investigate whether gene expression changes can be found in the blood of individuals with HD that distinguish them from healthy controls, we performed transcriptome analysis by next-generation sequencing (RNA-seq). We detected a gene expression signature consistent with dysregulation of immune-related functions and inflammatory response in peripheral blood from HD cases vs. controls, including induction of the interferon response genes, IFITM3, IFI6 and IRF7. Our results suggest that it is possible to detect gene expression changes in blood samples from individuals with HD, which may reflect the immune pathology associated with the disease.

scholarly journals Huntington's Disease: An Immune Perspective

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Annapurna Nayak ◽  
Rafia Ansar ◽  
Sunil K. Verma ◽  
Domenico Marco Bonifati ◽  
Uday Kishore
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Typical Feature ◽  
Trinucleotide Repeats ◽  
Mutant Huntingtin Protein ◽  
Unexplored Area ◽  
Cag Trinucleotide Repeats ◽  
The Brain ◽  
Abnormal Expansion

Huntington's disease (HD) is a progressive neurodegenerative disorder that is caused by abnormal expansion of CAG trinucleotide repeats. Neuroinflammation is a typical feature of most neurodegenerative diseases that leads to an array of pathological changes within the affected areas in the brain. The neurodegeneration in HD is also caused by aberrant immune response in the presence of aggregated mutant huntingtin protein. The effects of immune activation in HD nervous system are a relatively unexplored area of research. This paper summarises immunological features associated with development and progression of HD.

“organic Personality Disorder” as Part of Early Neuropsychiatric Manifestations in Huntington’s Disease - a Case Report

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
J. Maia
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Psychiatric Symptoms ◽  
Age Of Onset ◽  
Neuropsychiatric Symptoms ◽  
Personality Change ◽  
Psychotic Symptoms ◽  
Autosomal Dominant Disorder ◽  
Neuropsychiatric Manifestations ◽  
Psychiatric Manifestations

Huntington's Disease (HD) is an inherited autosomal dominant disorder characterized by motor, cognitive and psychiatric symptomatology, being considered a paradigmatic neuropsychiatric disorder that includes all three components of the "Triadic Syndromes": dyskinesia, dementia and depression.Firstly described in 1872 as an "Hereditary Chorea" by George Huntington only in 1993 was its responsible gene identified. A person who inherits the HD gene will sooner or later develop the disease. the age of onset, early signs and rate of disease progression vary greatly from person to person.Neuropsychiatric symptoms are an integral part of HD and have been considered the earliest markers of the disease, presenting sometimes more than 10 years before a formal diagnosis is done. Patients may experience dysphoria, mood swings, agitation, irritability, hostile outbursts, psychotic symptoms and deep bouts of depression with suicidal ideation. Personality change is reported in 48% of the cases, with the paranoid subtype being described as the most prevalent. the clinical case presented illustrates a case of HD which started with insidious psychiatric symptoms and an important personality change.Despite a wide number of medications being prescribed to help control emotional, movement and behaviour problems, there is still no treatment to stop or reverse the course of the disease. Furthermore, psychiatric manifestations are often amenable to treatment, and relief of these symptoms may provide significant improvement in patient's and caregivers quality of life.A greater awarness of psychiatric manifestations of HD is essential to an earlier diagnosis and an optimized therapeutic approach.

Plasma Cytokine Levels in Relation to Neuropsychiatric Symptoms and Cognitive Dysfunction in Huntington’s disease

2016 ◽  
Vol 5 (4) ◽  
pp. 369-377 ◽  
Author(s):  
Jos A. Bouwens ◽  
Erik van Duijn ◽  
Christa M. Cobbaert ◽  
Raymund A.C. Roos ◽  
Roos C. van der Mast ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cognitive Dysfunction ◽  
Neuropsychiatric Symptoms ◽  
Plasma Cytokine ◽  
Cytokine Levels

scholarly journals Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington’s Disease Models

2021 ◽  
Vol 14 (10) ◽  
pp. 1044
Author(s):  
Letizia Pruccoli ◽  
Carlo Breda ◽  
Gabriella Teti ◽  
Mirella Falconi ◽  
Flaviano Giorgini ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Death ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Positive Impact ◽  
Neuroprotective Effects ◽  
Drosophila Model ◽  
Exon 1 ◽  
Transgenic Drosophila

Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene. This mutation leads to the production of mutant HTT (mHTT) protein which triggers neuronal death through several mechanisms. Here, we investigated the neuroprotective effects of esculetin (ESC), a bioactive phenolic compound, in an inducible PC12 model and a transgenic Drosophila melanogaster model of HD, both of which express mHTT fragments. ESC partially inhibited the progression of mHTT aggregation and reduced neuronal death through its ability to counteract the oxidative stress and mitochondria impairment elicited by mHTT in the PC12 model. The ability of ESC to counteract neuronal death was also confirmed in the transgenic Drosophila model. Although ESC did not modify the lifespan of the transgenic Drosophila, it still seemed to have a positive impact on the HD phenotype of this model. Based on our findings, ESC may be further studied as a potential neuroprotective agent in a rodent transgenic model of HD.

scholarly journals Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington’s disease

2020 ◽  
Author(s):  
Giulia Birolini ◽  
Marta Valenza ◽  
Ilaria Ottonelli ◽  
Alice Passoni ◽  
Monica Favagrossa ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Polymeric Nanoparticles ◽  
Cholesterol Biosynthesis ◽  
Hybrid Nanoparticles ◽  
Neural Cells ◽  
Peripheral Tissues ◽  
Brain Cholesterol ◽  
The Brain

AbstractSupplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the bloodbrain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.

scholarly journals Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

2021 ◽  
Vol 22 (22) ◽  
pp. 12499
Author(s):  
Chaebin Kim ◽  
Ali Yousefian-Jazi ◽  
Seung-Hye Choi ◽  
Inyoung Chang ◽  
Junghee Lee ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Involuntary Movement ◽  
Therapeutic Approaches ◽  
Exon 1 ◽  
Human Chromosome 4 ◽  
The Brain

Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.

scholarly journals Innovative Therapeutic Approaches for Huntington’s Disease: From Nucleic Acids to GPCR-Targeting Small Molecules

2021 ◽  
Vol 15 ◽  
Author(s):  
Hidetoshi Komatsu
Keyword(s):  
Nucleic Acid ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
High Throughput Screening ◽  
Neurodegenerative Disorder ◽  
Direct Injection ◽  
Cag Repeat ◽  
Great Promise ◽  
Nucleic Acid Delivery ◽  
Small Interfering Rnas

Huntington’s disease (HD) is a fatal neurodegenerative disorder due to an extraordinarily expanded CAG repeat in the huntingtin gene that confers a gain-of-toxic function in the mutant protein. There is currently no effective cure that attenuates progression and severity of the disease. Since HD is an inherited monogenic disorder, lowering the mutant huntingtin (mHTT) represents a promising therapeutic strategy. Huntingtin lowering strategies mostly focus on nucleic acid approaches, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). While these approaches seem to be effective, the drug delivery to the brain poses a great challenge and requires direct injection into the central nervous system (CNS) that results in substantial burden for patients. This review discusses the topics on Huntingtin lowering strategies with clinical trials in patients already underway and introduce an innovative approach that has the potential to deter the disease progression through the inhibition of GPR52, a striatal-enriched class A orphan G protein-coupled receptor (GPCR) that represents a promising therapeutic target for psychiatric disorders. Chemically simple, potent, and selective GPR52 antagonists have been discovered through high-throughput screening and subsequent structure-activity relationship studies. These small molecule antagonists not only diminish both soluble and aggregated mHTT in the striatum, but also ameliorate HD-like defects in HD mice. This therapeutic approach offers great promise as a novel strategy for HD therapy, while nucleic acid delivery still faces considerable challenges.

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