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Molecular Mechanisms on Huntington's Disease
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Molecular Mechanisms 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 27376

Special Issue Editor

Dr. KyoungJoo Cho

E-Mail Website
Guest Editor
Department of Biology (Neuroscience Laboratory), Kyonggi University, Suwon 16227, Republic of Korea
Interests: neurodegenerative disease; aging; cognitive impairment; Huntington’s disease; autophagy; innate immunity; PROTAC; nanobody
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Huntington’s disease (HD) is caused by mutant huntingtin (mHTT) protein that contains abnormally extended polyglutamine repeats. The pathological mHTT has been investigated the mechanisms in each brain region and also ameliorated the toxicity in the brain. Many factors have been implicated in HD including alterations in calcium handling, neurotrophic factor signaling, vesicle transport, ER maintenance, autophagy, and neuroinflammation that is little known in contrast to other neurodegenerative diseases. In HD, the striatum is most affected, which leads to initiate and control movements of the body, limbs, and eyes. Preferential striatal degeneration is a well-known character. Understanding the mechanism of selective neuronal loss is highly important for developing effective treatment. Posttranslational modifications in mHTT have considerably been devoted to multiple sites in the HTT region. Targeting DNA and RNA to modulate protein expression are progressing for molecular therapies targeting HTT expression based on understanding and recovering molecular mechanism.

This special issue focuses on the recent advances on the molecular mechanisms of HD. We warmly welcome submissions of original manuscripts and reviews.

Dr. KyoungJoo Cho
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

  • mutant Huntingtin
  • autophagy
  • aggregates
  • neuroinflammation
  • selectivity
  • molecular therapy
  • UPS
  • E3 ligase

Published Papers (4 papers)

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Research

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36 pages, 6808 KiB  
Article
A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development
by Jingyun Wu, Luisa Möhle, Thomas Brüning, Iván Eiriz, Muhammad Rafehi, Katja Stefan, Sven Marcel Stefan and Jens Pahnke
Int. J. Mol. Sci. 2022, 23(23), 14763; https://doi.org/10.3390/ijms232314763 - 25 Nov 2022
Cited by 8 | Viewed by 3125
Abstract
Huntington’s disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of [...] Read more.
Huntington’s disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175Δneo mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD. Full article
(This article belongs to the Special Issue Molecular Mechanisms on Huntington's Disease)
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17 pages, 3064 KiB  
Article
Structural Abnormalities of the Optic Nerve and Retina in Huntington’s Disease Pre-Clinical and Clinical Settings
by Iwona Mazur-Michałek, Katarzyna Kowalska, Daniel Zielonka, Marta Leśniczak-Staszak, Paulina Pietras, Witold Szaflarski, Mark Isalan and Michal Mielcarek
Int. J. Mol. Sci. 2022, 23(10), 5450; https://doi.org/10.3390/ijms23105450 - 13 May 2022
Cited by 5 | Viewed by 2033
Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related pathological remodelling has been reported in HD mouse models and HD carriers. In this study, we studied structural abnormalities in the optic nerve by employing [...] Read more.
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related pathological remodelling has been reported in HD mouse models and HD carriers. In this study, we studied structural abnormalities in the optic nerve by employing Spectral Domain Optical Coherence Tomography (SD-OCT) in pre-symptomatic HD carriers of Caucasian origin. Transmission Electron Microscopy (TEM) was used to investigate ultrastructural changes in the optic nerve of the well-established R6/2 mouse model at the symptomatic stage of the disease. We found that pre-symptomatic HD carriers displayed a significant reduction in the retinal nerve fibre layer (RNFL) thickness, including specific quadrants: superior, inferior and temporal, but not nasal. There were no other significant irregularities in the GCC layer, at the macula level and in the optic disc morphology. The ultrastructural analysis of the optic nerve in R6/2 mice revealed a significant thinning of the myelin sheaths, with a lamellar separation of the myelin, and a presence of myelonoid bodies. We also found a significant reduction in the thickness of myelin sheaths in peripheral nerves within the choroids area. Those ultrastructural abnormalities were also observed in HD photoreceptor cells that contained severely damaged membrane disks, with evident vacuolisation and swelling. Moreover, the outer segment of retinal layers showed a progressive disintegration. Our study explored structural changes of the optic nerve in pre- and clinical settings and opens new avenues for the potential development of biomarkers that would be of great interest in HD gene therapies. Full article
(This article belongs to the Special Issue Molecular Mechanisms on Huntington's Disease)
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16 pages, 3085 KiB  
Article
Heat Shock Factor 1 Directly Regulates Postsynaptic Scaffolding PSD-95 in Aging and Huntington’s Disease and Influences Striatal Synaptic Density
by Nicole Zarate, Taylor A. Intihar, Dahyun Yu, Jacob Sawyer, Wei Tsai, Maha Syed, Luke Carlson and Rocio Gomez-Pastor
Int. J. Mol. Sci. 2021, 22(23), 13113; https://doi.org/10.3390/ijms222313113 - 4 Dec 2021
Cited by 10 | Viewed by 2723
Abstract
PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. [...] Read more.
PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute reduction in cell lines and mice decreased PSD-95 expression. Furthermore, Hsf1(+/−) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions. Full article
(This article belongs to the Special Issue Molecular Mechanisms on Huntington's Disease)
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Review

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50 pages, 2293 KiB  
Review
New Avenues for the Treatment of Huntington’s Disease
by Amy Kim, Kathryn Lalonde, Aaron Truesdell, Priscilla Gomes Welter, Patricia S. Brocardo, Tatiana R. Rosenstock and Joana Gil-Mohapel
Int. J. Mol. Sci. 2021, 22(16), 8363; https://doi.org/10.3390/ijms22168363 - 4 Aug 2021
Cited by 57 | Viewed by 18464
Abstract
Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that [...] Read more.
Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. Despite being a genetic disorder with a known cause, several mechanisms are thought to contribute to neurodegeneration in HD, and numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. Although current clinical trials may lead to the identification or refinement of treatments that are likely to improve the quality of life of those living with HD, major efforts continue to be invested at the pre-clinical level, with numerous studies testing novel approaches that show promise as disease-modifying strategies. This review offers a detailed overview of the currently approved treatment options for HD and the clinical trials for this neurodegenerative disorder that are underway and concludes by discussing potential disease-modifying treatments that have shown promise in pre-clinical studies, including increasing neurotropic support, modulating autophagy, epigenetic and genetic manipulations, and the use of nanocarriers and stem cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms on Huntington's Disease)
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