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Molecular Mechanisms of Polyglutamine Diseases
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Molecular Mechanisms of Polyglutamine Diseases

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 January 2022) | Viewed by 11664

Special Issue Editor

Dr. Clévio Nóbrega

E-Mail Website
Guest Editor
Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, Faro, Portugal
Interests: gene therapy; polyglutamine diseases; ataxin-2; ataxin-3; neurodegeneration; stress granules
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Polyglutamine diseases comprise a group of nine inherited neurodegenerative disorders caused by an abnormal mutation of a CAG tract within the coding region of the causative gene. This abnormal repetition codifies for an abnormal glutamine tract in the respective protein, which tends to aggregate, forming intraneuronal inclusions that are a neuropathological feature of these diseases. Currently, there is no cure to stop or delay disease progression, which culminates with the death of the patients.

The genetic basis for the diseases is established, however, the molecular mechanisms leading to the neuronal dysfunction and degeneration observed in selected regions of the brain of these patients are not completely characterized. This knowledge is important to better design and test new therapies that could represent a hope for the patients and an opportunity to stop the disease progression.

In these special number, we expect to gather a group of research studies and reviews aiming to advance the current knowledge of polyglutamine disease molecular mechanisms, but also providing a view of potential treatments and future clinical trials.

Prof. Dr. Clévio Nóbrega
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

  • Polyglutamine diseases
  • Genetics
  • Huntington’s disease
  • Spinocerebellar ataxias
  • Neurodegeneration
  • Aggregation
  • Disease mechanisms
  • Disease models
  • Biomarkers
  • Therapeutic approaches

Published Papers (3 papers)

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Review

20 pages, 2047 KiB  
Review
Extracellular Vesicles Physiological Role and the Particular Case of Disease-Spreading Mechanisms in Polyglutamine Diseases
by Ricardo Moreira, Liliana S. Mendonça and Luís Pereira de Almeida
Int. J. Mol. Sci. 2021, 22(22), 12288; https://doi.org/10.3390/ijms222212288 - 13 Nov 2021
Cited by 2 | Viewed by 2499
Abstract
Recent research demonstrated pathological spreading of the disease-causing proteins from one focal point across other brain regions for some neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease. Spreading mediated by extracellular vesicles is one of the proposed disease-spreading mechanisms. Extracellular vesicles are cell [...] Read more.
Recent research demonstrated pathological spreading of the disease-causing proteins from one focal point across other brain regions for some neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease. Spreading mediated by extracellular vesicles is one of the proposed disease-spreading mechanisms. Extracellular vesicles are cell membrane-derived vesicles, used by cells for cell-to-cell communication and excretion of toxic components. Importantly, extracellular vesicles carrying pathological molecules, when internalized by “healthy” cells, may trigger pathological pathways and, consequently, promote disease spreading to neighboring cells. Polyglutamine diseases are a group of genetic neurodegenerative disorders characterized by the accumulation of mutant misfolded proteins carrying an expanded tract of glutamines, including Huntington’s and Machado–Joseph disease. The pathological spread of the misfolded proteins or the corresponding mutant mRNA has been explored. The understanding of the disease-spreading mechanism that plays a key role in the pathology progression of these diseases can result in the development of effective therapeutic approaches to stop disease progression, arresting the spread of the toxic components and disease aggravation. Therefore, the present review’s main focus is the disease-spreading mechanisms with emphasis on polyglutamine diseases and the putative role played by extracellular vesicles in this process. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Polyglutamine Diseases)
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17 pages, 670 KiB  
Review
Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias
by Ricardo Afonso-Reis, Inês T. Afonso and Clévio Nóbrega
Int. J. Mol. Sci. 2021, 22(8), 4249; https://doi.org/10.3390/ijms22084249 - 19 Apr 2021
Cited by 11 | Viewed by 4264
Abstract
Polyglutamine spinocerebellar ataxias (PolyQ SCAs) are a group of 6 rare autosomal dominant diseases, which arise from an abnormal CAG repeat expansion in the coding region of their causative gene. These neurodegenerative ataxic disorders are characterized by progressive cerebellar degeneration, which translates into [...] Read more.
Polyglutamine spinocerebellar ataxias (PolyQ SCAs) are a group of 6 rare autosomal dominant diseases, which arise from an abnormal CAG repeat expansion in the coding region of their causative gene. These neurodegenerative ataxic disorders are characterized by progressive cerebellar degeneration, which translates into progressive ataxia, the main clinical feature, often accompanied by oculomotor deficits and dysarthria. Currently, PolyQ SCAs treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression, which culminates with death. Over the last years, many promising gene therapy approaches were investigated in preclinical studies and could lead to a future treatment to stop or delay the disease development. Here, we summed up the most promising of these therapies, categorizing them in gene augmentation therapy, gene silencing strategies, and gene edition approaches. While several of the reviewed strategies are promising, there is still a gap from the preclinical results obtained and their translation to clinical studies. However, there is an increase in the number of approved gene therapies, as well as a constant development in their safety and efficacy profiles. Thus, it is expected that in a near future some of the promising strategies reviewed here could be tested in a clinical setting and if successful provide hope for SCAs patients. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Polyglutamine Diseases)
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16 pages, 1959 KiB  
Review
Emerging Roles of Exosomes in Huntington’s Disease
by Hanadi Ananbeh, Petr Vodicka and Helena Kupcova Skalnikova
Int. J. Mol. Sci. 2021, 22(8), 4085; https://doi.org/10.3390/ijms22084085 - 15 Apr 2021
Cited by 28 | Viewed by 4298
Abstract
Huntington’s disease (HD) is a rare hereditary autosomal dominant neurodegenerative disorder, which is caused by expression of mutant huntingtin protein (mHTT) with an abnormal number of glutamine repeats in its N terminus, and characterized by intracellular mHTT aggregates (inclusions) in the brain. Exosomes [...] Read more.
Huntington’s disease (HD) is a rare hereditary autosomal dominant neurodegenerative disorder, which is caused by expression of mutant huntingtin protein (mHTT) with an abnormal number of glutamine repeats in its N terminus, and characterized by intracellular mHTT aggregates (inclusions) in the brain. Exosomes are small extracellular vesicles that are secreted generally by all cell types and can be isolated from almost all body fluids such as blood, urine, saliva, and cerebrospinal fluid. Exosomes may participate in the spreading of toxic misfolded proteins across the central nervous system in neurodegenerative diseases. In HD, such propagation of mHTT was observed both in vitro and in vivo. On the other hand, exosomes might carry molecules with neuroprotective effects. In addition, due to their capability to cross blood-brain barrier, exosomes hold great potential as sources of biomarkers available from periphery or carriers of therapeutics into the central nervous system. In this review, we discuss the emerging roles of exosomes in HD pathogenesis, diagnosis, and therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Polyglutamine Diseases)
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