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 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 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 Bim contributes to the progression of Huntington’s disease-associated phenotypes

2019 ◽  
Vol 29 (2) ◽  
pp. 216-227
Author(s):  
Sheridan L Roberts ◽  
Tracey Evans ◽  
Yi Yang ◽  
Yuhua Fu ◽  
Robert W Button ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Death ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Brain Regions ◽  
Post Mortem ◽  
Polyglutamine Tract

Abstract Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin (HTT) protein. Mutant HTT (mHTT) toxicity is caused by its aggregation/oligomerization. The striatum is the most vulnerable region, although all brain regions undergo neuronal degeneration in the disease. Here we show that the levels of Bim, a BH3-only protein, are significantly increased in HD human post-mortem and HD mouse striata, correlating with neuronal death. Bim reduction ameliorates mHTT neurotoxicity in HD cells. In the HD mouse model, heterozygous Bim knockout significantly mitigates mHTT accumulation and neuronal death, ameliorating disease-associated phenotypes and lifespan. Therefore, Bim could contribute to the progression of HD.

scholarly journals Westphal Variant of Huntington's Disease

2017 ◽  
Vol 17 (01) ◽  
pp. 028-030
Author(s):  
L. Cabarcas-Castro ◽  
J. Ramón-Gómez ◽  
A. Zarante-Bahamón ◽  
O. Bernal-Pacheco ◽  
E. Espinosa-García ◽  
...  
Keyword(s):  
Family History ◽  
Huntington's Disease ◽  
Movement Disorder ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cag Repeats ◽  
Molecular Evidence ◽  
Exon 1 ◽  
History Of

AbstractA Westphal variant of Huntington's disease (HD) is an infrequent presentation of this inherited neurodegenerative disorder. Here, we describe a 14-year-old girl who developed symptoms at the age of 7, with molecular evidence of abnormally expanded Cytosine-Adenine-Guanine (CAG) repeats in exon 1 of the Huntingtin gene. We briefly review the classical features of this variant highlighting the importance of suspecting HD in a child with parkinsonism and a family history of movement disorder or dementia.

Huntington’s disease

2020 ◽  
pp. 83-92
Author(s):  
Juliana R Dutra ◽  
Tanya P Garcia ◽  
Karen Marder
Keyword(s):  
Clinical Trials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Genetic Mutation ◽  
Current Standard ◽  
Disease Modifying ◽  
Disease Modifying Agents ◽  
A Current

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder caused by an unstable expansion in the cytosine adenine guanine (CAG) trinucleotide repeat in the huntingtin gene. The disease onsets gradually over many years and its symptoms include extrapyramidal movement disorder, cognitive impairment, and behavioural changes. Understanding the overall progression of HD is critical to designing clinical trials with possible disease modifying agents. Research in this area has exploded in the past two decades, as different multicentre studies have evaluated both clinical and biological measures in individuals at different stages of the disease (i.e. at-risk for the genetic mutation, pre-manifest, and manifest HD). In this chapter, we provide readers with a current understanding of HD progression. This includes an overview of the current standard for how HD is clinically evaluated, descriptive epidemiology of the disease, genetics of HD, and a review of potential disease modifiers.

Rab8 Promotes Mutant HTT Aggregation, Reduces Neurodegeneration, and Ameliorates Behavioural Alterations in a Drosophila Model of Huntington’s Disease

2020 ◽  
Vol 9 (3) ◽  
pp. 253-263
Author(s):  
Laura Delfino ◽  
Robert P. Mason ◽  
Charalambos P. Kyriacou ◽  
Flaviano Giorgini ◽  
Ezio Rosato
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Vesicle Trafficking ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Cellular Processes ◽  
Drosophila Model ◽  
Molecular Phenotypes ◽  
Photoreceptor Neurons

Background: Altered cellular vesicle trafficking has been linked to the pathogenesis of Huntington’s disease (HD), a fatal, inherited neurodegenerative disorder caused by mutation of the huntingtin (HTT) protein. The Rab GTPase family of proteins plays a key role in regulation of vesicle trafficking, with distinct Rabs helping specify membrane identity and mediating cellular processes including budding, motility and tethering of vesicles to their targets. In recent years several Rab GTPases—notably, Rab5 and Rab11—have been linked to the pathogenesis of neurodegenerative disorders, including HD. Objective: We investigated whether Rab8, which regulates post-Golgi vesicle trafficking, is able to improve HD-relevant phenotypes in a well-characterised model. Methods: We overexpressed Rab8 in a Drosophila model of HD testing cellular, behavioural, and molecular phenotypes. Results: We found that Rab8 overexpression ameliorated several disease-related phenotypes in fruit flies expressing a mutant HTT fragment throughout the nervous system, including neurodegeneration of photoreceptor neurons, reduced eclosion of the adult fly from the pupal case and shortened lifespan. Rab8 overexpression also normalised aberrant circadian locomotor behaviour in flies expressing mutant HTT in a specific population of neurons that regulate the circadian clock. Intriguingly, expression of Rab8 increased the accumulation of SDS-insoluble aggregated species of mutant HTT. Conclusion: Collectively, our findings demonstrate that increased Rab8 levels protect against mutant HTT toxicity and potentiate its aggregation, likely reducing the accumulation of downstream toxic soluble species.

Huntington's disease: molecular basis of neurodegeneration

2003 ◽  
Vol 5 (20) ◽  
pp. 1-21 ◽  
Author(s):  
David C. Rubinsztein ◽  
Jenny Carmichael
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Current Status ◽  
Soluble Form ◽  
Polyglutamine Expansion ◽  
Wide Range ◽  
Polyglutamine Tract ◽  
Hd Gene

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product (‘huntingtin’). Studies in humans and mouse models suggest that the mutation is associated with a deleterious gain-of-function. Several studies have suggested that the large huntingtin protein is cleaved to produce a shorter N-terminal fragment containing the polyglutamine expansion, and that the polyglutamine expansion causes the protein fragment to misfold and form aggregates (inclusions) in the nuclei and processes of neurons. It is likely that neurotoxicity is caused by the misfolded protein in its soluble form, and/or in aggregates, and/or in the process of aggregation. A wide range of potential mechanisms for neurotoxicity have been proposed, including caspase activation, dysregulation of transcriptional pathways, increased production of reactive oxygen species, and inhibition of proteasome activity. In this review we consider the current status of research in the field and possible mechanisms whereby the HD mutation might result in neurodegeneration.

scholarly journals D1R- and D2R-Medium-Sized Spiny Neurons Diversity: Insights Into Striatal Vulnerability to Huntington’s Disease Mutation

2021 ◽  
Vol 15 ◽  
Author(s):  
Guendalina Bergonzoni ◽  
Jessica Döring ◽  
Marta Biagioli
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Neuronal Population ◽  
Specific Gene ◽  
Spiny Neurons ◽  
Loss Of Autonomy ◽  
Exon 1 ◽  
Cell Type Specific ◽  
Gene Expression Dysregulation

Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an aberrant expansion of the CAG tract within the exon 1 of the HD gene, HTT. HD progressively impairs motor and cognitive capabilities, leading to a total loss of autonomy and ultimate death. Currently, no cure or effective treatment is available to halt the disease. Although the HTT gene is ubiquitously expressed, the striatum appears to be the most susceptible district to the HD mutation with Medium-sized Spiny Neurons (MSNs) (D1R and D2R) representing 95% of the striatal neuronal population. Why are striatal MSNs so vulnerable to the HD mutation? Particularly, why do D1R- and D2R-MSNs display different susceptibility to HD? Here, we highlight significant differences between D1R- and D2R-MSNs subpopulations, such as morphology, electrophysiology, transcriptomic, functionality, and localization in the striatum. We discuss possible reasons for their selective degeneration in the context of HD. Our review suggests that a better understanding of cell type-specific gene expression dysregulation within the striatum might reveal new paths to therapeutic intervention or prevention to ameliorate HD patients’ life expectancy.

Effect of luteolin on the transgenic Drosophila model of Huntington’s disease

2021 ◽  
Vol 17 ◽  
pp. 100148
Author(s):  
Yasir Hasan Siddique ◽  
Rahul ◽  
Himanshi Varshney ◽  
I. Mantasha ◽  
M. Shahid
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Drosophila Model ◽  
Transgenic Drosophila

scholarly journals Emerging Roles of Exosomes in Huntington’s Disease

2021 ◽  
Vol 22 (8) ◽  
pp. 4085
Author(s):  
Hanadi Ananbeh ◽  
Petr Vodicka ◽  
Helena Kupcova Skalnikova
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cell Types ◽  
Neuroprotective Effects ◽  
The Central Nervous System

Huntington’s disease (HD) is a rare hereditary autosomal dominant neurodegenerative disorder, which is caused by expression of mutant huntingtin protein (mHTT) with an abnormal number of glutamine repeats in its N terminus, and characterized by intracellular mHTT aggregates (inclusions) in the brain. Exosomes are small extracellular vesicles that are secreted generally by all cell types and can be isolated from almost all body fluids such as blood, urine, saliva, and cerebrospinal fluid. Exosomes may participate in the spreading of toxic misfolded proteins across the central nervous system in neurodegenerative diseases. In HD, such propagation of mHTT was observed both in vitro and in vivo. On the other hand, exosomes might carry molecules with neuroprotective effects. In addition, due to their capability to cross blood-brain barrier, exosomes hold great potential as sources of biomarkers available from periphery or carriers of therapeutics into the central nervous system. In this review, we discuss the emerging roles of exosomes in HD pathogenesis, diagnosis, and therapy.

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