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Huntington’s Disease: Molecular Advances in Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 11942

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Special Issue Editors

Dr. Silvia Romano

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Guest Editor

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, 00189 Rome, Italy
Interests: Huntington’s disease

Dr. Elide Mantuano

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Guest Editor

Institute of Translational Pharmacology, National Research Council, 00133 Rome, Italy
Interests: Huntington’s disease

Dr. Simona Petrucci

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Guest Editor

Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, Viale Regina Elena 291, 00161 Rome, Italy
Interests: Huntington’s disease

Special Issue Information

Dear Colleagues,

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion in exon 1 of the HTT gene encoding the huntingtin protein. The mutant protein contains an expanded polyglutamine sequence that confers a toxic gain-of-function and causes neurodegeneration.

HD is a progressive, incurable disease with a typical adult onset characterized by motor impairment, cognitive dysfunction, and psychiatric symptoms. In current practice, clinical onset of HD is classified as the beginning of motor abnormalities using the diagnostic confidence level (DCL). The disease course before onset has been defined by several terms, including the presymptomatic, premanifest, or prodromal phases, and is characterized by MRI abnormalities and/or psychiatric, behavioural, and cognitive dysfunction.

Despite the identification of the genetic defect causing HD almost 30 years ago, to date there are no effective disease-modifying treatments; currently available drugs address the disease symptoms and aim to control motor and behavioural abnormalities, but have limited benefits and do not address disease progression.

The search for more efficient therapies has been marked by promising results in preclinical research and many clinical failures, such as the recent early termination of the antisense oligonucleotide tominersen trials.

Although the new gene silencing approaches have been found to be effective in some genetic diseases, such as spinal muscular atrophy, their application has not yet been established in HD. Their beneficial effects are not clear, and many side effects occur due to the routes of administration (intrathecal or intracerebral). In the absence of specific data and considering the complexity of the disease, a combined approach using several drugs acting selectively and differentially on different pathways, particularly in subjects with overt pathology, should be considered.

This Special Issue will focus on the latest advances in establishing new promising molecular-based therapeutical approaches for HD. We welcome the submission of original research and review articles depicting new pharmacotherapies and their applications or potential gene therapies for the treatment of Huntington’s disease.

Dr. Silvia Romano
Dr. Elide Mantuano
Dr. Simona Petrucci
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

preclinical and translational studies
therapy
therapeutical targets
gene therapy
pharmacotherapy
molecular mechanisms
biomarkers

Published Papers (5 papers)

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Research

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14 pages, 4413 KiB

Open AccessArticle

Cell-Type Specific Regulation of Cholesterogenesis by CYP46A1 Re-Expression in zQ175 HD Mouse Striatum

by Katleen Pinchaud, Chloé Masson, Baptiste Dayre, Coline Mounier, Jean-François Gilles, Peter Vanhoutte, Jocelyne Caboche and Sandrine Betuing

Int. J. Mol. Sci. 2023, 24(13), 11001; https://doi.org/10.3390/ijms241311001 - 02 Jul 2023

Viewed by 1354

Abstract

Cholesterol metabolism dysregulation is associated with several neurological disorders. In Huntington’s disease (HD), several enzymes involved in cholesterol metabolism are downregulated, among which the neuronal cholesterol 24-hydroxylase, CYP46A1, is of particular interest. The restoration of CYP46A1 expression in striatal neurons of HD mouse models is beneficial for motor behavior, cholesterol metabolism, transcriptomic activity, and alleviates neuropathological hallmarks induced by mHTT. Among the genes regulated after CYP46A1 restoration, those involved in cholesterol synthesis and efflux may explain the positive effect of CYP46A1 on cholesterol precursor metabolites. Since cholesterol homeostasis results from a fine-tuning between neurons and astrocytes, we quantified the distribution of key genes regulating cholesterol metabolism and efflux in astrocytes and neurons using in situ hybridization coupled with S100β and NeuN immunostaining, respectively. Neuronal expression of CYP46A1 in the striatum of HD zQ175 mice increased key cholesterol synthesis driver genes (Hmgcr, Dhcr24), specifically in neurons. This effect was associated with an increase of the srebp2 transcription factor gene that regulates most of the genes encoding for cholesterol enzymes. However, the cholesterol efflux gene, ApoE, was specifically upregulated in astrocytes by CYP46A1, probably though a paracrine effect. In summary, the neuronal expression of CYP46A1 has a dual and specific effect on neurons and astrocytes, regulating cholesterol metabolism. The neuronal restoration of CYP46A1 in HD paves the way for future strategies to compensate for mHTT toxicity. Full article

(This article belongs to the Special Issue Huntington’s Disease: Molecular Advances in Therapeutics)

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9 pages, 3433 KiB

Open AccessCommunication

Treatment with the Glycosphingolipid Modulator THI Rescues Myelin Integrity in the Striatum of R6/2 HD Mice

by Giuseppe Pepe, Paola Lenzi, Luca Capocci, Federico Marracino, Ludovica Pizzati, Pamela Scarselli, Alba Di Pardo, Francesco Fornai and Vittorio Maglione

Int. J. Mol. Sci. 2023, 24(6), 5956; https://doi.org/10.3390/ijms24065956 - 22 Mar 2023

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Abstract

Huntington’s disease is one of the most common dominantly inherited neurodegenerative disorders caused by an expansion of a polyglutamine (polyQ) stretch in the N-terminal region of huntingtin (Htt). Among all the molecular mechanisms, affected by the mutation, emerging evidence proposes glycosphingolipid dysfunction as one of the major determinants. High levels of sphingolipids have been found to localize in the myelin sheaths of oligodendrocytes, where they play an important role in myelination stability and functions. In this study, we investigated any potential existing link between sphingolipid modulation and myelin structure by performing both ultrastructural and biochemical analyses. Our findings demonstrated that the treatment with the glycosphingolipid modulator THI preserved myelin thickness and the overall structure and reduced both area and diameter of pathologically giant axons in the striatum of HD mice. These ultrastructural findings were associated with restoration of different myelin marker protein, such as myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and 2′, 3′ Cyclic Nucleotide 3′-Phosphodiesterase (CNP). Interestingly, the compound modulated the expression of glycosphingolipid biosynthetic enzymes and increased levels of GM1, whose elevation has been extensively reported to be associated with reduced toxicity of mutant Htt in different HD pre-clinical models. Our study further supports the evidence that the metabolism of glycosphingolipids may represent an effective therapeutic target for the disease. Full article

(This article belongs to the Special Issue Huntington’s Disease: Molecular Advances in Therapeutics)

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29 pages, 14222 KiB

Open AccessArticle

Integrated Bioinformatics Analysis of Shared Genes, miRNA, Biological Pathways and Their Potential Role as Therapeutic Targets in Huntington’s Disease Stages

by Christiana C. Christodoulou and Eleni Zamba Papanicolaou

Int. J. Mol. Sci. 2023, 24(5), 4873; https://doi.org/10.3390/ijms24054873 - 02 Mar 2023

Cited by 2 | Viewed by 2291

Abstract

Huntington’s Disease (HD) is a progressive neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT). The HTT gene was the first disease-associated gene mapped to a chromosome, but the pathophysiological mechanisms, genes, proteins or miRNAs involved in HD remain poorly understood. Systems bioinformatics approaches can divulge the synergistic relationships of multiple omics data and their integration, and thus provide a holistic approach to understanding diseases. The purpose of this study was to identify the differentially expressed genes (DEGs), HD-related gene targets, pathways and miRNAs in HD and, more specifically, between the pre-symptomatic and symptomatic HD stages. Three publicly available HD datasets were analysed to obtain DEGs for each HD stage from each dataset. In addition, three databases were used to obtain HD-related gene targets. The shared gene targets between the three public databases were compared, and clustering analysis was performed on the common shared genes. Enrichment analysis was performed on (i) DEGs identified for each HD stage in each dataset, (ii) gene targets from the public databases and (iii) the clustering analysis results. Furthermore, the hub genes shared between the public databases and the HD DEGs were identified, and topological network parameters were applied. Identification of HD-related miRNAs and their gene targets was obtained, and a miRNA-gene network was constructed. Enriched pathways identified for the 128 common genes revealed pathways linked to multiple neurodegeneration diseases (HD, Parkinson’s disease, Spinocerebellar ataxia), MAPK and HIF-1 signalling pathways. Eighteen HD-related hub genes were identified based on network topological analysis of MCC, degree and closeness. The highest-ranked genes were FoxO3 and CASP3, CASP3 and MAP2 were found for betweenness and eccentricity and CREBBP and PPARGC1A were identified for the clustering coefficient. The miRNA-gene network identified eleven miRNAs (mir-19a-3p, mir-34b-3p, mir-128-5p, mir-196a-5p, mir-34a-5p, mir-338-3p, mir-23a-3p and mir-214-3p) and eight genes (ITPR1, CASP3, GRIN2A, FoxO3, TGM2, CREBBP, MTHFR and PPARGC1A). Our work revealed that various biological pathways seem to be involved in HD either during the pre-symptomatic or symptomatic stages of HD. This may offer some clues for the molecular mechanisms, pathways and cellular components underlying HD and how these may act as potential therapeutic targets for HD. Full article

(This article belongs to the Special Issue Huntington’s Disease: Molecular Advances in Therapeutics)

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Review

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33 pages, 1543 KiB

Open AccessReview

Brain–Periphery Interactions in Huntington’s Disease: Mediators and Lifestyle Interventions

by Johannes Burtscher, Barbara Strasser, Giuseppe Pepe, Martin Burtscher, Martin Kopp, Alba Di Pardo, Vittorio Maglione and Andy V. Khamoui

Int. J. Mol. Sci. 2024, 25(9), 4696; https://doi.org/10.3390/ijms25094696 - 25 Apr 2024

Viewed by 275

Abstract

Prominent pathological features of Huntington’s disease (HD) are aggregations of mutated Huntingtin protein (mHtt) in the brain and neurodegeneration, which causes characteristic motor (such as chorea and dystonia) and non-motor symptoms. However, the numerous systemic and peripheral deficits in HD have gained increasing attention recently, since those factors likely modulate disease progression, including brain pathology. While whole-body metabolic abnormalities and organ-specific pathologies in HD have been relatively well described, the potential mediators of compromised inter-organ communication in HD have been insufficiently characterized. Therefore, we applied an exploratory literature search to identify such mediators. Unsurprisingly, dysregulation of inflammatory factors, circulating mHtt, and many other messenger molecules (hormones, lipids, RNAs) were found that suggest impaired inter-organ communication, including of the gut–brain and muscle–brain axis. Based on these findings, we aimed to assess the risks and potentials of lifestyle interventions that are thought to improve communication across these axes: dietary strategies and exercise. We conclude that appropriate lifestyle interventions have great potential to reduce symptoms and potentially modify disease progression (possibly via improving inter-organ signaling) in HD. However, impaired systemic metabolism and peripheral symptoms warrant particular care in the design of dietary and exercise programs for people with HD. Full article

(This article belongs to the Special Issue Huntington’s Disease: Molecular Advances in Therapeutics)

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46 pages, 3157 KiB

Open AccessReview

From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research

by Andrew Jiang, Renee R. Handley, Klaus Lehnert and Russell G. Snell

Int. J. Mol. Sci. 2023, 24(16), 13021; https://doi.org/10.3390/ijms241613021 - 21 Aug 2023

Cited by 6 | Viewed by 6085

Abstract

Huntington’s disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as a highly penetrant dominant disorder likely acting through a toxic gain of function by the mutant huntingtin protein. Widespread cellular degeneration of the medium spiny neurons of the caudate nucleus and putamen are responsible for the onset of symptomology that encompasses motor, cognitive, and behavioural abnormalities. Over the past 150 years of HD research since George Huntington published his description, a plethora of pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption of proteostasis, transcriptional dysregulation, and neuroinflammation. Despite the identification and characterisation of the causative gene and mutation and significant advances in our understanding of the cellular pathology in recent years, a disease-modifying intervention has not yet been clinically approved. This review includes an overview of Huntington’s disease, from its genetic aetiology to clinical presentation and its pathogenic manifestation. An updated view of molecular mechanisms and the latest therapeutic developments will also be discussed. Full article

(This article belongs to the Special Issue Huntington’s Disease: Molecular Advances in Therapeutics)

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