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Molecular Research on Huntington’s Disease
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Molecular Research on Huntington’s Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 18797

Special Issue Editors

Dr. Luis M. Valor

E-Mail Website
Guest Editor
Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain
Interests: Huntington’s disease; trinucleotide expansions; epigenetics; transcription
Dr. Antonio Campos-Caro

E-Mail
Guest Editor
Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain
Interests: Huntington's Disease

Special Issue Information

Dear Colleagues,

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an aberrant expansion of CAG repeats at the HTT exon 1 locus, which mainly affects the basal ganglia in patients. Despite knowing the cause of the disease, an effective cure is still elusive. However, extensive research has been conducted in the recent years to elucidate the etiopathogenic mechanisms that are triggered as a consequence of the production of an mHTT polyglutamine peptide and the loss of a functional allele, which in combination, alter multiple cellular processes (e.g., transcription and epigenetics, mitochondrial respiration, proteasomal degradation, vesicle trafficking, neurotransmitter release, etc.) that cumulatively compromise cell viability and the survival. Although neurons are specially affected, the functionality of other cell types can also be relevant in the disease. In this Special Issue, we intend to provide an updated overview of the most prominent molecular events that are behind the complex symptomatology in HD patients, by including original research and reviews that describe molecular mechanisms that have been modelled in cellular preparations and genetically modified animals with a clear potential to be translated into the clinics by proposing biomarkers of prognosis aimed at improving clinical counselling and disease monitoring and/or therapeutical approaches for amelioration of the disease in patients.

Dr. Luis M. Valor
Dr. Antonio Campos-Caro
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Huntington’s disease
  • molecular mechanisms
  • biomarkers
  • therapeutical targets
  • preclinical and translational studies
  • patients

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

2 pages, 175 KiB  
Editorial
Molecular Research on Huntington’s Disease
by Luis M. Valor
Int. J. Mol. Sci. 2023, 24(5), 4310; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054310 - 21 Feb 2023
Viewed by 1096
Abstract
Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an aberrant expansion of CAG triplets in the HTT (Huntingtin) gene [...] Full article
(This article belongs to the Special Issue Molecular Research on Huntington’s Disease)

Research

Jump to: Editorial, Review

14 pages, 4162 KiB  
Article
Analysis of Huntington’s Disease Modifiers Using the Hyperbolic Mapping of the Protein Interaction Network
by Aimilia-Christina Vagiona, Pablo Mier, Spyros Petrakis and Miguel A. Andrade-Navarro
Int. J. Mol. Sci. 2022, 23(10), 5853; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105853 - 23 May 2022
Cited by 5 | Viewed by 2232
Abstract
Huntington’s disease (HD) is caused by the production of a mutant huntingtin (HTT) with an abnormally long poly-glutamine (polyQ) tract, forming aggregates and inclusions in neurons. Previous work by us and others has shown that an increase or decrease in polyQ-triggered aggregates can [...] Read more.
Huntington’s disease (HD) is caused by the production of a mutant huntingtin (HTT) with an abnormally long poly-glutamine (polyQ) tract, forming aggregates and inclusions in neurons. Previous work by us and others has shown that an increase or decrease in polyQ-triggered aggregates can be passive simply due to the interaction of proteins with the aggregates. To search for proteins with active (functional) effects, which might be more effective in finding therapies and mechanisms of HD, we selected among the proteins that interact with HTT a total of 49 pairs of proteins that, while being paralogous to each other (and thus expected to have similar passive interaction with HTT), are located in different regions of the protein interaction network (suggesting participation in different pathways or complexes). Three of these 49 pairs contained members with opposite effects on HD, according to the literature. The negative members of the three pairs, MID1, IKBKG, and IKBKB, interact with PPP2CA and TUBB, which are known negative factors in HD, as well as with HSP90AA1 and RPS3. The positive members of the three pairs interact with HSPA9. Our results provide potential HD modifiers of functional relevance and reveal the dynamic aspect of paralog evolution within the interaction network. Full article
(This article belongs to the Special Issue Molecular Research on Huntington’s Disease)
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19 pages, 22361 KiB  
Article
Identification of Novel Therapeutic Targets for Polyglutamine Diseases That Target Mitochondrial Fragmentation
by Annika Traa, Emily Machiela, Paige D. Rudich, Sonja K. Soo, Megan M. Senchuk and Jeremy M. Van Raamsdonk
Int. J. Mol. Sci. 2021, 22(24), 13447; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413447 - 14 Dec 2021
Cited by 7 | Viewed by 2547
Abstract
Huntington’s disease (HD) is one of at least nine polyglutamine diseases caused by a trinucleotide CAG repeat expansion, all of which lead to age-onset neurodegeneration. Mitochondrial dynamics and function are disrupted in HD and other polyglutamine diseases. While multiple studies have found beneficial [...] Read more.
Huntington’s disease (HD) is one of at least nine polyglutamine diseases caused by a trinucleotide CAG repeat expansion, all of which lead to age-onset neurodegeneration. Mitochondrial dynamics and function are disrupted in HD and other polyglutamine diseases. While multiple studies have found beneficial effects from decreasing mitochondrial fragmentation in HD models by disrupting the mitochondrial fission protein DRP1, disrupting DRP1 can also have detrimental consequences in wild-type animals and HD models. In this work, we examine the effect of decreasing mitochondrial fragmentation in a neuronal C. elegans model of polyglutamine toxicity called Neur-67Q. We find that Neur-67Q worms exhibit mitochondrial fragmentation in GABAergic neurons and decreased mitochondrial function. Disruption of drp-1 eliminates differences in mitochondrial morphology and rescues deficits in both movement and longevity in Neur-67Q worms. In testing twenty-four RNA interference (RNAi) clones that decrease mitochondrial fragmentation, we identified eleven clones—each targeting a different gene—that increase movement and extend lifespan in Neur-67Q worms. Overall, we show that decreasing mitochondrial fragmentation may be an effective approach to treating polyglutamine diseases and we identify multiple novel genetic targets that circumvent the potential negative side effects of disrupting the primary mitochondrial fission gene drp-1. Full article
(This article belongs to the Special Issue Molecular Research on Huntington’s Disease)
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20 pages, 2714 KiB  
Article
C57BL/6 Background Attenuates mHTT Toxicity in the Striatum of YAC128 Mice
by Michaela K. Back, Johanna Kurzawa, Sonia Ruggieri and Jakob von Engelhardt
Int. J. Mol. Sci. 2021, 22(23), 12664; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312664 - 23 Nov 2021
Cited by 4 | Viewed by 1886
Abstract
Mouse models are frequently used to study Huntington’s disease (HD). The onset and severity of neuronal and behavioral pathologies vary greatly between HD mouse models, which results from different huntingtin expression levels and different CAG repeat length. HD pathology appears to depend also [...] Read more.
Mouse models are frequently used to study Huntington’s disease (HD). The onset and severity of neuronal and behavioral pathologies vary greatly between HD mouse models, which results from different huntingtin expression levels and different CAG repeat length. HD pathology appears to depend also on the strain background of mouse models. Thus, behavioral deficits of HD mice are more severe in the FVB than in the C57BL/6 background. Alterations in medium spiny neuron (MSN) morphology and function have been well documented in young YAC128 mice in the FVB background. Here, we tested the relevance of strain background for mutant huntingtin (mHTT) toxicity on the cellular level by investigating HD pathologies in YAC128 mice in the C57BL/6 background (YAC128/BL6). Morphology, spine density, synapse function and membrane properties were not or only subtly altered in MSNs of 12-month-old YAC128/BL6 mice. Despite the mild cellular phenotype, YAC128/BL6 mice showed deficits in motor performance. More pronounced alterations in MSN function were found in the HdhQ150 mouse model in the C57BL/6 background (HdhQ150/BL6). Consistent with the differences in HD pathology, the number of inclusion bodies was considerably lower in YAC128/BL6 mice than HdhQ150/BL6 mice. This study highlights the relevance of strain background for mHTT toxicity in HD mouse models. Full article
(This article belongs to the Special Issue Molecular Research on Huntington’s Disease)
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Review

Jump to: Editorial, Research

17 pages, 394 KiB  
Review
A New Perspective on Huntington’s Disease: How a Neurological Disorder Influences the Peripheral Tissues
by Laura Gómez-Jaramillo, Fátima Cano-Cano, María del Carmen González-Montelongo, Antonio Campos-Caro, Manuel Aguilar-Diosdado and Ana I. Arroba
Int. J. Mol. Sci. 2022, 23(11), 6089; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116089 - 29 May 2022
Cited by 7 | Viewed by 2954
Abstract
Huntington’s disease (HD) is a neurodegenerative disorder caused by a toxic, aggregation-prone expansion of CAG repeats in the HTT gene with an age-dependent progression that leads to behavioral, cognitive and motor symptoms. Principally affecting the frontal cortex and the striatum, mHTT disrupts many [...] Read more.
Huntington’s disease (HD) is a neurodegenerative disorder caused by a toxic, aggregation-prone expansion of CAG repeats in the HTT gene with an age-dependent progression that leads to behavioral, cognitive and motor symptoms. Principally affecting the frontal cortex and the striatum, mHTT disrupts many cellular functions. In fact, increasing evidence shows that peripheral tissues are affected by neurodegenerative diseases. It establishes an active crosstalk between peripheral tissues and the brain in different neurodegenerative diseases. This review focuses on the current knowledge of peripheral tissue effects in HD animal and cell experimental models and identifies biomarkers and mechanisms involved or affected in the progression of the disease as new therapeutic or early diagnostic options. The particular changes in serum/plasma, blood cells such as lymphocytes, immune blood cells, the pancreas, the heart, the retina, the liver, the kidney and pericytes as a part of the blood–brain barrier are described. It is important to note that several changes in different mouse models of HD present differences between them and between the different ages analyzed. The understanding of the impact of peripheral organ inflammation in HD may open new avenues for the development of novel therapeutic targets. Full article
(This article belongs to the Special Issue Molecular Research on Huntington’s Disease)
15 pages, 375 KiB  
Review
A Glimpse of Molecular Biomarkers in Huntington’s Disease
by Silvia Martí-Martínez and Luis M. Valor
Int. J. Mol. Sci. 2022, 23(10), 5411; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105411 - 12 May 2022
Cited by 12 | Viewed by 3394
Abstract
Huntington’s disease (HD) is a devastating neurodegenerative disorder that is caused by an abnormal expansion of CAG repeats in the Huntingtin (HTT) gene. Although the main symptomatology is explained by alterations at the level of the central nervous system, predominantly affecting [...] Read more.
Huntington’s disease (HD) is a devastating neurodegenerative disorder that is caused by an abnormal expansion of CAG repeats in the Huntingtin (HTT) gene. Although the main symptomatology is explained by alterations at the level of the central nervous system, predominantly affecting the basal ganglia, a peripheral component of the disease is being increasingly acknowledged. Therefore, the manifestation of the disease is complex and variable among CAG expansion carriers, introducing uncertainty in the appearance of specific signs, age of onset and severity of disease. The monogenic nature of the disorder allows a precise diagnosis, but the use of biomarkers with prognostic value is still needed to achieve clinical management of the patients in an individual manner. In addition, we need tools to evaluate the patient’s response to potential therapeutic approaches. In this review, we provide a succinct summary of the most interesting molecular biomarkers that have been assessed in patients, mostly obtained from body fluids such as cerebrospinal fluid, peripheral blood and saliva. Full article
(This article belongs to the Special Issue Molecular Research on Huntington’s Disease)
25 pages, 18567 KiB  
Review
Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease
by Chaebin Kim, Ali Yousefian-Jazi, Seung-Hye Choi, Inyoung Chang, Junghee Lee and Hoon Ryu
Int. J. Mol. Sci. 2021, 22(22), 12499; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212499 - 19 Nov 2021
Cited by 8 | Viewed by 3841
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Research on Huntington’s Disease)
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