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Huntingtin: Interacting Proteins, Degradation, Post-translational Modifications

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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 8166

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Special Issue Editor

Prof. Dr. Stephan Von Hörsten

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Guest Editor

Dept Experimental Therapy, Universitätsklinikum Erlangen, 91054 Erlangen, Germany
Interests: alpha-synuclein (α-synuclein); huntington disease; neuropeptides; Alzheimer’s disease; amyloid-beta (Aβ)

Special Issue Information

Dear Colleagues,

The neurodegenerative disorder Huntington’s disease is caused by an expansion in the polyglutamine repeat region of the protein huntingtin. Recent studies have identified several huntingtin-interacting proteins that might be associated with the normal function of huntingtin and/or involved in the pathology of Huntington’s disease. However, the normal function of huntingtin, an essential cellular protein in higher vertebrates, is not yet well understood. In this Special Issue, we focus on the degradation, post-translational modifications of Huntingtin, as well as its potential roles of huntingtin–protein interactions in the pathogenesis of Huntington’s disease.

We invite researchers of all fields—physicians, pharmacologists, biologists, chemists, etc.—to present their results and propose prospective applications by contributing original research articles or review papers.

Prof. Dr. Stephan Von Hörsten
Guest Editor

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
Huntington’s disease
protein interaction
protein degradation
post-translational modifications

Published Papers (5 papers)

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Research

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14 pages, 7781 KiB

Open AccessArticle

Deregulated Transcriptome as a Platform for Adrenal Huntington’s Disease-Related Pathology

by Anna Olechnowicz, Małgorzata Blatkiewicz, Karol Jopek, Mark Isalan, Michal Mielcarek and Marcin Rucinski

Int. J. Mol. Sci. 2024, 25(4), 2176; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25042176 - 11 Feb 2024

Viewed by 665

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder that affects mainly the central nervous system (CNS) by inducing progressive deterioration in both its structure and function. In recent years, there has been growing interest in the impact of HD on peripheral tissue function. Herein, we used the R6/2 mouse model of HD to investigate the influence of the disease on adrenal gland functioning. A transcriptomic analysis conducted using a well-established quantitative method, an Affymetrix array, revealed changes in gene expression in the R6/2 model compared to genetic background controls. For the first time, we identified disruptions in cholesterol and sterol metabolism, blood coagulation, and xenobiotic metabolism in HD adrenal glands. This study showed that the disrupted expression of these genes may contribute to the underlying mechanisms of Huntington’s disease. Our findings may contribute to developing a better understanding of Huntington’s disease progression and aid in the development of novel diagnostic or therapeutic approaches. Full article

(This article belongs to the Special Issue Huntingtin: Interacting Proteins, Degradation, Post-translational Modifications)

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23 pages, 4600 KiB

Open AccessArticle

Truncated Analogues of a G-Quadruplex-Forming Aptamer Targeting Mutant Huntingtin: Shorter Is Better!

by Claudia Riccardi, Federica D’Aria, Dominga Fasano, Filomena Anna Digilio, Maria Rosaria Carillo, Jussara Amato, Laura De Rosa, Simona Paladino, Mariarosa Anna Beatrice Melone, Daniela Montesarchio and Concetta Giancola

Int. J. Mol. Sci. 2022, 23(20), 12412; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012412 - 17 Oct 2022

Cited by 5 | Viewed by 1517

Abstract

Two analogues of the MS3 aptamer, which was previously shown to have an exquisite capability to selectively bind and modulate the activity of mutant huntingtin (mHTT), have been here designed and evaluated in their physicochemical and biological properties. Featured by a distinctive propensity to form complex G-quadruplex structures, including large multimeric aggregates, the original 36-mer MS3 has been truncated to give a 33-mer (here named MS3-33) and a 17-mer (here named MS3-17). A combined use of different techniques (UV, CD, DSC, gel electrophoresis) allowed a detailed physicochemical characterization of these novel G-quadruplex-forming aptamers, tested in vitro on SH-SY5Y cells and in vivo on a Drosophila Huntington’s disease model, in which these shorter MS3-derived oligonucleotides proved to have improved bioactivity in comparison with the parent aptamer. Full article

(This article belongs to the Special Issue Huntingtin: Interacting Proteins, Degradation, Post-translational Modifications)

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Review

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17 pages, 1734 KiB

Open AccessReview

Huntingtin Interacting Proteins and Pathological Implications

by Li Liu, Huichun Tong, Yize Sun, Xingxing Chen, Tianqi Yang, Gongke Zhou, Xiao-Jiang Li and Shihua Li

Int. J. Mol. Sci. 2023, 24(17), 13060; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713060 - 22 Aug 2023

Viewed by 1526

Abstract

Huntington’s disease (HD) is caused by an expansion of a CAG repeat in the gene that encodes the huntingtin protein (HTT). The exact function of HTT is still not fully understood, and previous studies have mainly focused on identifying proteins that interact with HTT to gain insights into its function. Numerous HTT-interacting proteins have been discovered, shedding light on the functions and structure of HTT. Most of these proteins interact with the N-terminal region of HTT. Among the various HTT-interacting proteins, huntingtin-associated protein 1 (HAP1) and HTT-interacting protein 1 (HIP1) have been extensively studied. Recent research has uncovered differences in the distribution of HAP1 in monkey and human brains compared with mice. This finding suggests that there may be species-specific variations in the regulation and function of HTT-interacting proteins. Understanding these differences could provide crucial insights into the development of HD. In this review, we will focus on the recent advancements in the study of HTT-interacting proteins, with particular attention to the differential distributions of HTT and HAP1 in larger animal models. Full article

(This article belongs to the Special Issue Huntingtin: Interacting Proteins, Degradation, Post-translational Modifications)

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13 pages, 2482 KiB

Open AccessReview

The Mystery of EVP4593: Perspectives of the Quinazoline-Derived Compound in the Treatment of Huntington’s Disease and Other Human Pathologies

by Dmitriy A. Grekhnev, Anna A. Kruchinina, Vladimir A. Vigont and Elena V. Kaznacheyeva

Int. J. Mol. Sci. 2022, 23(24), 15724; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415724 - 11 Dec 2022

Cited by 3 | Viewed by 1943

Abstract

Quinazoline derivatives have various pharmacological activities and are widely used in clinical practice. Here, we reviewed the proposed mechanisms of the physiological activity of the quinazoline derivative EVP4593 and perspectives for its clinical implication. We summarized the accumulated data about EVP4593 and focused on its activities in different models of Huntington’s disease (HD), including patient-specific iPSCs-based neurons. To make a deeper insight into its neuroprotective role in HD treatment, we discussed the ability of EVP4593 to modulate calcium signaling and reduce the level of the huntingtin protein. Moreover, we described possible protective effects of EVP4593 in other pathologies, such as oncology, cardiovascular diseases and parasite invasion. We hope that comprehensive analyses of the molecular mechanisms of EVP4593 activity will allow for the expansion of the scope of the EVP4593 application. Full article

(This article belongs to the Special Issue Huntingtin: Interacting Proteins, Degradation, Post-translational Modifications)

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21 pages, 1440 KiB

Open AccessReview

Huntingtin and Other Neurodegeneration-Associated Proteins in the Development of Intracellular Pathologies: Potential Target Search for Therapeutic Intervention

by Aleksandra S. Churkina (Taran), Anton S. Shakhov, Anatoly A. Kotlobay and Irina B. Alieva

Int. J. Mol. Sci. 2022, 23(24), 15533; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415533 - 08 Dec 2022

Cited by 2 | Viewed by 1895

Abstract

Neurodegenerative diseases are currently incurable. Numerous experimental data accumulated over the past fifty years have brought us closer to understanding the molecular and cell mechanisms responsible for their development. However, these data are not enough for a complete understanding of the genesis of these diseases, nor to suggest treatment methods. It turns out that many cellular pathologies developing during neurodegeneration coincide from disease to disease. These observations give hope to finding a common intracellular target(s) and to offering a universal method of treatment. In this review, we attempt to analyze data on similar cellular disorders among neurodegenerative diseases in general, and polyglutamine neurodegenerative diseases in particular, focusing on the interaction of various proteins involved in the development of neurodegenerative diseases with various cellular organelles. The main purposes of this review are: (1) to outline the spectrum of common intracellular pathologies and to answer the question of whether it is possible to find potential universal target(s) for therapeutic intervention; (2) to identify specific intracellular pathologies and to speculate about a possible general approach for their treatment. Full article

(This article belongs to the Special Issue Huntingtin: Interacting Proteins, Degradation, Post-translational Modifications)

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