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Biomedicines
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Breaking Down Huntington’s Disease: Molecular Mechanisms, Biomarkers and Therapeutic Strategies
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Breaking Down Huntington’s Disease: Molecular Mechanisms, Biomarkers and Therapeutic Strategies

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 10224

Special Issue Editors

Dr. Esther Pérez-Navarro

E-Mail Website
Guest Editor
Dept. Biomedical Sciences, Faculty of Medicine and Health Sciences, Inst. Neurociencies, Univ. Barcelona, Casanova 143, E-08036 Barcelona, Catalonia, Spain
Interests: Huntington’s disease; motor and cognitive behavior; molecular mechanisms; therapeutic targets identification; biomarkers
Dr. Jordi Creus-Muncunill

E-Mail Website
Guest Editor
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Interests: Huntington's disease; movement disorders; neurodegeneration; cell death; RNA toxicity; inflammation; transcriptomic; epigenomics

Special Issue Information

Dear Colleagues,

Huntington’s disease (HD) is a dominant inherited neurodegenerative disorder caused by unstable expansion of a CAG repeat within the exon 1 in the Huntingtin gene. This results in an extended polyglutamine tract in the huntingtin protein that induces a cascade of toxic events leading to neuronal dysfunction and neurodegeneration. Although motor symptoms are the most prominent, psychiatric alterations and cognitive decline appear earlier in HD patients, and become more evident as the disease progresses. The fact that symptoms are so diverse and variable between patients makes the establishment of a unique and effective therapy challenging. Moreover, the molecular bases that account for the dysfunction/degeneration of specific neuronal populations remain elusive. Therefore, the knowledge of the molecular mechanisms involved in the pathophysiology can help to identify therapeutic targets. Another important concern when designing a therapy is when to start the treatment since HD is characterized by a late onset of symptoms, by which time neuronal degeneration is already irreversible. Although the age of onset inversely correlates with the number of CAG repeats, it is still unpredictable. Therefore, the identification of biomarkers for diagnosis, prognosis or progression would allow for identifying the best time window to start treatment thus increasing the possible efficacy of the therapy in stopping or ameliorating neurodegeneration.

This Special Issue will focus on the latest advances in the knowledge of molecular mechanisms involved in the pathophysiology of HD and the identification of biomarkers, and how their interconnection could serve as a basis to establish new therapeutical approaches for HD.

Dr. Esther Pérez-Navarro
Dr. Jordi Creus-Muncunill
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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
  • therapy
  • neuronal dysfunction and/or degeneration
  • motor dysfunction
  • cognitive dysfunction

Published Papers (4 papers)

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Research

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19 pages, 3584 KiB  
Article
Postnatal Conditional Deletion of Bcl11b in Striatal Projection Neurons Mimics the Transcriptional Signature of Huntington’s Disease
by Sicheng Song, Jordi Creus Muncunill, Carlos Galicia Aguirre, Kizito-Tshitoko Tshilenge, B. Wade Hamilton, Akos A. Gerencser, Houda Benlhabib, Maria-Daniela Cirnaru, Mark Leid, Sean D. Mooney, Lisa M. Ellerby and Michelle E. Ehrlich
Biomedicines 2022, 10(10), 2377; https://doi.org/10.3390/biomedicines10102377 - 23 Sep 2022
Cited by 2 | Viewed by 2312
Abstract
The dysregulation of striatal gene expression and function is linked to multiple diseases, including Huntington’s disease (HD), Parkinson’s disease, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neurons in the striatum and are critical [...] Read more.
The dysregulation of striatal gene expression and function is linked to multiple diseases, including Huntington’s disease (HD), Parkinson’s disease, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neurons in the striatum and are critical to motor control. The transcription factor, Bcl11b (also known as Ctip2), is required for striatal development, but the function of Bcl11b in adult MSNs in vivo has not been investigated. We conditionally deleted Bcl11b specifically in postnatal MSNs and performed a transcriptomic and behavioral analysis on these mice. Multiple enrichment analyses showed that the D9-Cre-Bcl11btm1.1Leid transcriptional profile was similar to the HD gene expression in mouse and human data sets. A Gene Ontology enrichment analysis linked D9-Cre-Bcl11btm1.1Leid to calcium, synapse organization, specifically including the dopaminergic synapse, protein dephosphorylation, and HDAC-signaling, commonly dysregulated pathways in HD. D9-Cre-Bcl11btm1.1Leid mice had decreased DARPP-32/Ppp1r1b in MSNs and behavioral deficits, demonstrating the dysregulation of a subtype of the dopamine D2 receptor expressing MSNs. Finally, in human HD isogenic MSNs, the mislocalization of BCL11B into nuclear aggregates points to a mechanism for BCL11B loss of function in HD. Our results suggest that BCL11B is important for the function and maintenance of mature MSNs and Bcl11b loss of function drives, in part, the transcriptomic and functional changes in HD. Full article
(This article belongs to the Special Issue Breaking Down Huntington’s Disease: Molecular Mechanisms, Biomarkers and Therapeutic Strategies)
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16 pages, 2091 KiB  
Article
CAG Repeat Instability in the Peripheral and Central Nervous System of Transgenic Huntington’s Disease Monkeys
by In K. Cho, Faye Clever, Gordon Hong and Anthony W. S. Chan
Biomedicines 2022, 10(8), 1863; https://doi.org/10.3390/biomedicines10081863 - 2 Aug 2022
Cited by 1 | Viewed by 2341
Abstract
Huntington’s Disease (HD) is an autosomal dominant disease that results in severe neurodegeneration with no cure. HD is caused by the expanded CAG trinucleotide repeat (TNR) on the Huntingtin gene (HTT). Although the somatic and germline expansion of the CAG repeats [...] Read more.
Huntington’s Disease (HD) is an autosomal dominant disease that results in severe neurodegeneration with no cure. HD is caused by the expanded CAG trinucleotide repeat (TNR) on the Huntingtin gene (HTT). Although the somatic and germline expansion of the CAG repeats has been well-documented, the underlying mechanisms had not been fully delineated. Increased CAG repeat length is associated with a more severe phenotype, greater TNR instability, and earlier age of onset. The direct relationship between CAG repeat length and molecular pathogenesis makes TNR instability a useful measure of symptom severity and tissue susceptibility. Thus, we examined the tissue-specific TNR instability of transgenic nonhuman primate models of Huntington’s disease. Our data show a similar profile of CAG repeat expansion in both rHD1 and rHD7, where high instability was observed in testis, liver, caudate, and putamen. CAG repeat expansion was observed in all tissue samples, and tissue- and CAG repeat size-dependent expansion was observed. Correlation analysis of CAG repeat expansion and the gene expression profile of four genes in different tissues, clusterin (CLU), transferrin (TF), ribosomal protein lateral stalk subunit P1 (RPLP1), and ribosomal protein L13a (RPL13A), showed a strong correlation with CAG repeat instability. Overall, our data, along with previously published studies, can be used for studying the biology of CAG repeat instability and identifying new therapeutic targets. Full article
(This article belongs to the Special Issue Breaking Down Huntington’s Disease: Molecular Mechanisms, Biomarkers and Therapeutic Strategies)
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17 pages, 3239 KiB  
Article
Temporal Characterization of Behavioral and Hippocampal Dysfunction in the YAC128 Mouse Model of Huntington’s Disease
by Cristine de Paula Nascimento-Castro, Elisa C. Winkelmann-Duarte, Gianni Mancini, Priscilla Gomes Welter, Evelini Plácido, Marcelo Farina, Joana Gil-Mohapel, Ana Lúcia S. Rodrigues, Andreza Fabro de Bem and Patricia S. Brocardo
Biomedicines 2022, 10(6), 1433; https://doi.org/10.3390/biomedicines10061433 - 17 Jun 2022
Cited by 2 | Viewed by 2653
Abstract
Huntington’s disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal [...] Read more.
Huntington’s disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal characterization of the behavioral and hippocampal dysfunctions. Early and late symptomatic YAC128 mice exhibited depressive-like behavior, as demonstrated by increased immobility times in the Tail Suspension Test. In addition, YAC128 mice exhibited cognitive deficits in the Swimming T-maze Test during the late symptomatic stage. Except for a reduction in basal mitochondrial respiration, no significant deficits in the mitochondrial respiratory rates were observed in the hippocampus of late symptomatic YAC128 mice. In agreement, YAC128 animals did not present robust alterations in mitochondrial ultrastructural morphology. However, light and electron microscopy analysis revealed the presence of dark neurons characterized by the intense staining of granule cell bodies and shrunken nuclei and cytoplasm in the hippocampal dentate gyrus (DG) of late symptomatic YAC128 mice. Furthermore, structural alterations in the rough endoplasmic reticulum and Golgi apparatus were detected in the hippocampal DG of YAC128 mice by electron microscopy. These results clearly show a degenerative process in the hippocampal DG in late symptomatic YAC128 animals. Full article
(This article belongs to the Special Issue Breaking Down Huntington’s Disease: Molecular Mechanisms, Biomarkers and Therapeutic Strategies)
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Review

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25 pages, 1926 KiB  
Review
Protein Kinase CK2 and Its Potential Role as a Therapeutic Target in Huntington’s Disease
by Angel White, Anna McGlone and Rocio Gomez-Pastor
Biomedicines 2022, 10(8), 1979; https://doi.org/10.3390/biomedicines10081979 - 15 Aug 2022
Cited by 4 | Viewed by 2361
Abstract
Huntington’s Disease (HD) is a devastating neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, for which no disease modifying therapies are currently available. Much of the recent research has focused on developing therapies to directly lower HTT expression, [...] Read more.
Huntington’s Disease (HD) is a devastating neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, for which no disease modifying therapies are currently available. Much of the recent research has focused on developing therapies to directly lower HTT expression, and while promising, these therapies have presented several challenges regarding administration and efficacy. Another promising therapeutic approach is the modulation of HTT post-translational modifications (PTMs) that are dysregulated in disease and have shown to play a key role in HTT toxicity. Among all PTMs, modulation of HTT phosphorylation has been proposed as an attractive therapeutic option due to the possibility of orally administering specific kinase effectors. One of the kinases described to participate in HTT phosphorylation is Protein Kinase CK2. CK2 has recently emerged as a target for the treatment of several neurological and psychiatric disorders, although its role in HD remains controversial. While pharmacological studies in vitro inhibiting CK2 resulted in reduced HTT phosphorylation and increased toxicity, genetic approaches in mouse models of HD have provided beneficial effects. In this review we discuss potential therapeutic approaches related to the manipulation of HTT-PTMs with special emphasis on the role of CK2 as a therapeutic target in HD. Full article
(This article belongs to the Special Issue Breaking Down Huntington’s Disease: Molecular Mechanisms, Biomarkers and Therapeutic Strategies)
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