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Molecular Basis and Molecular Targets in Huntington’s Disease

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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 (31 December 2020) | Viewed by 33446

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Special Issue Editors

Dr. Veronica Morea

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Guest Editor

Institute of Molecular Biology and Pathology of The National Research Council of Italy, Rome, Italy
Interests: computational determination of relationships between protein sequence, 3D structure, and function; rational design of protein variants and peptides for biomedical purposes; model building of protein 3D structures from sequence; assignment of function to protein 3D structures and sequences

Dr. Andrea Ilari

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Guest Editor

Institute of Molecular Biology and Pathology of The National Research Council of Italy, Rome, Italy
Interests: structure–function relationships in proteins; protein structure determination by X-ray crystallography; enzimatic assays; inhibition studies; structure-based drug design; neurodegenerative diseases

Dr. Gianni Colotti

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Guest Editor

Institute of Molecular Biology and Pathology of The National Research Council of Italy, Rome, Italy
Interests: study of relationships between structure and function of proteins; study of physicochemical properties of proteins; protein–protein interactions; molecular biophysics techniques; structure-based drug discovery; molecular bases of diseases; calcium-binding proteins; cell signaling; proteins involved in cellular stress; calcium in physiological and pathological conditions; stress in cancer and neurodegenerative diseases

Special Issue Information

Dear Colleagues,

Huntington’s disease (HD) is the most common inherited, dominantly transmitted, neurodegenerative disorder. It is characterized by motor, behavior, and psychiatric symptoms, ultimately leading to death.

The disease is caused by abnormal expansion of a CAG triplet in the gene encoding the huntingtin (Htt) protein, with consequent expansion of a polyglutamine repeat in mutated Htt (mHtt). However, a number of crucial questions concerning the mechanism(s) leading to disease onset, including the function of Htt itself, are yet to be answered.

This Special Issue will collect original research articles and reviews focused on physiological and pathological aspects of HD, with a special emphasis on the underlying molecular mechanisms, with the aim of prompting the elaboration of novel concepts aimed at the development of novel therapeutic strategies.

Please, don’t hesitate to contact us if you have any questions.

Looking forward to hearing from you.

Dr. Veronica Morea
Dr. Andrea Ilari
Dr. Gianni Colotti
Guest Editors

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Keywords

Huntington’s disease (HD)
molecular mechanisms
molecular targets
huntingtin (Htt)
mutated Htt (mHtt)
Htt interacting molecules (Htt-IM)
Htt modifying molecules (Htt-MM)
bioinformatics
structural biology
cellular models
animal models

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Published Papers (9 papers)

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Research

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27 pages, 103523 KiB

Open AccessArticle

In Silico Analysis of Huntingtin Homologs in Lower Eukaryotes

by Valentina Brandi and Fabio Polticelli

Int. J. Mol. Sci. 2021, 22(6), 3214; https://doi.org/10.3390/ijms22063214 - 22 Mar 2021

Cited by 1 | Viewed by 2311

Abstract

Huntington’s disease is a rare neurodegenerative and autosomal dominant disorder. HD is caused by a mutation in the gene coding for huntingtin (Htt). The result is the production of a mutant Htt with an abnormally long polyglutamine repeat that leads to pathological Htt aggregates. Although the structure of human Htt has been determined, albeit at low resolution, its functions and how they are performed are largely unknown. Moreover, there is little information on the structure and function of Htt in other organisms. The comparison of Htt homologs can help to understand if there is a functional conservation of domains in the evolution of Htt in eukaryotes. In this work, through a computational approach, Htt homologs from lower eukaryotes have been analysed, identifying ordered domains and modelling their structure. Based on the structural models, a putative function for most of the domains has been predicted. A putative C. elegans Htt-like protein has also been analysed following the same approach. The results obtained support the notion that this protein is a orthologue of human Htt. Full article

(This article belongs to the Special Issue Molecular Basis and Molecular Targets in Huntington’s Disease)

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13 pages, 3459 KiB

Open AccessArticle

Huntingtin: A Protein with a Peculiar Solvent Accessible Surface

by Giulia Babbi, Castrense Savojardo, Pier Luigi Martelli and Rita Casadio

Int. J. Mol. Sci. 2021, 22(6), 2878; https://doi.org/10.3390/ijms22062878 - 12 Mar 2021

Cited by 3 | Viewed by 2360

Abstract

Taking advantage of the last cryogenic electron microscopy structure of human huntingtin, we explored with computational methods its physicochemical properties, focusing on the solvent accessible surface of the protein and highlighting a quite interesting mix of hydrophobic and hydrophilic patterns, with the prevalence of the latter ones. We then evaluated the probability of exposed residues to be in contact with other proteins, discovering that they tend to cluster in specific regions of the protein. We then found that the remaining portions of the protein surface can contain calcium-binding sites that we propose here as putative mediators for the protein to interact with membranes. Our findings are justified in relation to the present knowledge of huntingtin functional annotation. Full article

(This article belongs to the Special Issue Molecular Basis and Molecular Targets in Huntington’s Disease)

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20 pages, 29018 KiB

Open AccessArticle

The Role of Low Complexity Regions in Protein Interaction Modes: An Illustration in Huntingtin

by Kristina Kastano, Pablo Mier and Miguel A. Andrade-Navarro

Int. J. Mol. Sci. 2021, 22(4), 1727; https://doi.org/10.3390/ijms22041727 - 9 Feb 2021

Cited by 16 | Viewed by 3559

Abstract

Low complexity regions (LCRs) are very frequent in protein sequences, generally having a lower propensity to form structured domains and tending to be much less evolutionarily conserved than globular domains. Their higher abundance in eukaryotes and in species with more cellular types agrees with a growing number of reports on their function in protein interactions regulated by post-translational modifications. LCRs facilitate the increase of regulatory and network complexity required with the emergence of organisms with more complex tissue distribution and development. Although the low conservation and structural flexibility of LCRs complicate their study, evolutionary studies of proteins across species have been used to evaluate their significance and function. To investigate how to apply this evolutionary approach to the study of LCR function in protein–protein interactions, we performed a detailed analysis for Huntingtin (HTT), a large protein that is a hub for interaction with hundreds of proteins, has a variety of LCRs, and for which partial structural information (in complex with HAP40) is available. We hypothesize that proteins RASA1, SYN2, and KAT2B may compete with HAP40 for their attachment to the core of HTT using similar LCRs. Our results illustrate how evolution might favor the interplay of LCRs with domains, and the possibility of detecting multiple modes of LCR-mediated protein–protein interactions with a large hub such as HTT when enough protein interaction data is available. Full article

(This article belongs to the Special Issue Molecular Basis and Molecular Targets in Huntington’s Disease)

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13 pages, 2689 KiB

Open AccessArticle

A Novel Triplet-Primed PCR Assay to Detect the Full Range of Trinucleotide CAG Repeats in the Huntingtin Gene (HTT)

by Alessandro De Luca, Annunziata Morella, Federica Consoli, Sergio Fanelli, Julie R. Thibert, Sarah Statt, Gary J. Latham and Ferdinando Squitieri

Int. J. Mol. Sci. 2021, 22(4), 1689; https://doi.org/10.3390/ijms22041689 - 8 Feb 2021

Cited by 12 | Viewed by 5952

Abstract

The expanded CAG repeat number in HTT gene causes Huntington disease (HD), which is a severe, dominant neurodegenerative illness. The accurate determination of the expanded allele size is crucial to confirm the genetic status in symptomatic and presymptomatic at-risk subjects and avoid genetic polymorphism-related false-negative diagnoses. Precise CAG repeat number determination is critical to discriminate the cutoff between unexpanded and intermediate mutable alleles (IAs, 27–35 CAG) as well as between IAs and pathological, low-penetrance alleles (i.e., 36–39 CAG repeats), and it is also critical to detect large repeat expansions causing pediatric HD variants. We analyzed the HTT-CAG repeat number of 14 DNA reference materials and of a DNA collection of 43 additional samples carrying unexpanded, IAs, low and complete penetrance alleles, including large (>60 repeats) and very large (>100 repeats) expansions using a novel triplet-primed PCR-based assay, the AmplideX PCR/CE HTT Kit. The results demonstrate that the method accurately genotypes both normal and expanded HTT-CAG repeat numbers and reveals previously undisclosed and very large CAG expansions >200 repeats. We also show that this technique can improve genetic test reliability and accuracy by detecting CAG expansions in samples with sequence variations within or adjacent to the repeat tract that cause allele drop-outs or inaccuracies using other PCR methods. Full article

(This article belongs to the Special Issue Molecular Basis and Molecular Targets in Huntington’s Disease)

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26 pages, 5726 KiB

Open AccessArticle

Known Drugs Identified by Structure-Based Virtual Screening Are Able to Bind Sigma-1 Receptor and Increase Growth of Huntington Disease Patient-Derived Cells

by Theo Battista, Gianmarco Pascarella, David Sasah Staid, Gianni Colotti, Jessica Rosati, Annarita Fiorillo, Alessia Casamassa, Angelo Luigi Vescovi, Barbara Giabbai, Marta Stefania Semrau, Sergio Fanelli, Paola Storici, Ferdinando Squitieri, Veronica Morea and Andrea Ilari

Int. J. Mol. Sci. 2021, 22(3), 1293; https://doi.org/10.3390/ijms22031293 - 28 Jan 2021

Cited by 6 | Viewed by 3467

Abstract

Huntington disease (HD) is a devastating and presently untreatable neurodegenerative disease characterized by progressively disabling motor and mental manifestations. The sigma-1 receptor (σ1R) is a protein expressed in the central nervous system, whose 3D structure has been recently determined by X-ray crystallography and whose agonists have been shown to have neuroprotective activity in neurodegenerative diseases. To identify therapeutic agents against HD, we have implemented a drug repositioning strategy consisting of: (i) Prediction of the ability of the FDA-approved drugs publicly available through the ZINC database to interact with σ1R by virtual screening, followed by computational docking and visual examination of the 20 highest scoring drugs; and (ii) Assessment of the ability of the six drugs selected by computational analyses to directly bind purified σ1R in vitro by Surface Plasmon Resonance and improve the growth of fibroblasts obtained from HD patients, which is significantly impaired with respect to control cells. All six of the selected drugs proved able to directly bind purified σ1R in vitro and improve the growth of HD cells from both or one HD patient. These results support the validity of the drug repositioning procedure implemented herein for the identification of new therapeutic tools against HD. Full article

(This article belongs to the Special Issue Molecular Basis and Molecular Targets in Huntington’s Disease)

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13 pages, 2486 KiB

Open AccessArticle

Curcumin-Loaded Nanoparticles Based on Amphiphilic Hyaluronan-Conjugate Explored as Targeting Delivery System for Neurodegenerative Disorders

by Giuseppe Pepe, Enrica Calce, Valentina Verdoliva, Michele Saviano, Vittorio Maglione, Alba Di Pardo and Stefania De Luca

Int. J. Mol. Sci. 2020, 21(22), 8846; https://doi.org/10.3390/ijms21228846 - 23 Nov 2020

Cited by 19 | Viewed by 3049

Abstract

Identification of molecules able to promote neuroprotective mechanisms can represent a promising therapeutic approach to neurodegenerative disorders including Huntington’s disease. Curcumin is an antioxidant and neuroprotective agent, even though its efficacy is limited by its poor absorption, rapid metabolism, systemic elimination, and limited blood–brain barrier (BBB) permeability. Herein, we report on novel biodegradable curcumin-containing nanoparticles to favor the compound delivery and potentially enhance its brain bioavailability. The prepared hyaluronan-based materials able to self-assemble in stable spherical nanoparticles, consist of natural fatty acids chemically conjugated to the natural polysaccharide. The aim of this study is to provide a possible effective delivery system for curcumin with the expectation that, after having released the drug at the specific site, the biopolymer can degrade to nontoxic fragments before renal excretion, since all the starting materials are provided by natural resource. Our findings demonstrate that curcumin-encapsulated nanoparticles enter the cells and reduce their susceptibility to apoptosis in an in vitro model of Huntington’s disease. Full article

(This article belongs to the Special Issue Molecular Basis and Molecular Targets in Huntington’s Disease)

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8 pages, 975 KiB

Open AccessArticle

Mitochondrial Respiration Changes in R6/2 Huntington’s Disease Model Mice during Aging in a Brain Region Specific Manner

by Johannes Burtscher, Alba Di Pardo, Vittorio Maglione, Christoph Schwarzer and Ferdinando Squitieri

Int. J. Mol. Sci. 2020, 21(15), 5412; https://doi.org/10.3390/ijms21155412 - 30 Jul 2020

Cited by 13 | Viewed by 2747

Abstract

Mitochondrial dysfunction is crucially involved in aging and neurodegenerative diseases, such as Huntington’s Disease (HD). How mitochondria become compromised in HD is poorly understood but instrumental for the development of treatments to prevent or reverse resulting deficits. In this paper, we investigate whether oxidative phosphorylation (OXPHOS) differs across brain regions in juvenile as compared to adult mice and whether such developmental changes might be compromised in the R6/2 mouse model of HD. We study OXPHOS in the striatum, hippocampus, and motor cortex by high resolution respirometry in female wild-type and R6/2 mice of ages corresponding to pre-symptomatic and symptomatic R6/2 mice. We observe a developmental shift in OXPHOS-control parameters that was similar in R6/2 mice, except for cortical succinate-driven respiration. While the LEAK state relative to maximal respiratory capacity was reduced in adult mice in all analyzed brain regions, succinate-driven respiration was reduced only in the striatum and cortex, and NADH-driven respiration was higher as compared to juvenile mice only in the striatum. We demonstrate age-related changes in respirational capacities of different brain regions with subtle deviations in R6/2 mice. Uncovering in situ oxygen conditions and potential substrate limitations during aging and HD disease progression are interesting avenues for future research to understand brain-regional vulnerability in HD. Full article

(This article belongs to the Special Issue Molecular Basis and Molecular Targets in Huntington’s Disease)

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27 pages, 825 KiB

Open AccessReview

Molecular Mechanisms Underlying Muscle Wasting in Huntington’s Disease

by Manuela Bozzi and Francesca Sciandra

Int. J. Mol. Sci. 2020, 21(21), 8314; https://doi.org/10.3390/ijms21218314 - 5 Nov 2020

Cited by 20 | Viewed by 5123

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by pathogenic expansions of the triplet cytosine-adenosine-guanosine (CAG) within the Huntingtin gene. These expansions lead to a prolongation of the poly-glutamine stretch at the N-terminus of Huntingtin causing protein misfolding and aggregation. Huntingtin and its pathological variants are widely expressed, but the central nervous system is mainly affected, as proved by the wide spectrum of neurological symptoms, including behavioral anomalies, cognitive decline and motor disorders. Other hallmarks of HD are loss of body weight and muscle atrophy. This review highlights some key elements that likely provide a major contribution to muscle atrophy, namely, alteration of the transcriptional processes, mitochondrial dysfunction, which is strictly correlated to loss of energy homeostasis, inflammation, apoptosis and defects in the processes responsible for the protein quality control. The improvement of muscular symptoms has proven to slow the disease progression and extend the life span of animal models of HD, underlining the importance of a deep comprehension of the molecular mechanisms driving deterioration of muscular tissue. Full article

(This article belongs to the Special Issue Molecular Basis and Molecular Targets in Huntington’s Disease)

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7 pages, 1308 KiB

Open AccessCommentary

Implications of the Orb2 Amyloid Structure in Huntington’s Disease

by Rubén Hervás, Alexey G. Murzin and Kausik Si

Int. J. Mol. Sci. 2020, 21(18), 6910; https://doi.org/10.3390/ijms21186910 - 21 Sep 2020

Cited by 3 | Viewed by 3227

Abstract

Huntington’s disease is a progressive, autosomal dominant, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. As a result, the translated protein, huntingtin, contains an abnormally long polyglutamine stretch that makes it prone to misfold and aggregating. Aggregation of huntingtin is believed to be the cause of Huntington’s disease. However, understanding on how, and why, huntingtin aggregates are deleterious has been hampered by lack of enough relevant structural data. In this review, we discuss our recent findings on a glutamine-based functional amyloid isolated from Drosophila brain and how this information provides plausible structural insight on the structure of huntingtin deposits in the brain. Full article

(This article belongs to the Special Issue Molecular Basis and Molecular Targets in Huntington’s Disease)

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