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Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0
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Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 14354

Special Issue Editors

Prof. Dr. Teresa Zoladek

E-Mail Website
Guest Editor
Institute of Biochemistry and Biophysics of the Polish Academy of Sciences, Warsaw, Poland
Interests: VPS13; Yeast Models
Special Issues, Collections and Topics in MDPI journals
Dr. Joanna Kaminska

E-Mail Website
Guest Editor
Institute of Biochemistry and Biophysics of the Polish Academy of Sciences, Warsaw, Poland
Interests: VPS13; Yeast Models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are a group of age-related diseases characterized by a progressive loss of neurons, which is manifested by a decline of motor and/or cognitive function. The most common neurodegenerative diseases are Alzheimer’s, Parkinson’s, and Huntington’s disease, in which the presence of protein aggregates containing amyloid β, α-synuclein, and huntingtin, respectively, as well as defects in various cellular processes, such as vesicle trafficking, iron homeostasis, and mitochondrial function, are described. These diseases are frequently studied, while much less attention has been paid to neurodegenerative diseases that are very rare. For example, the ultra-rare neurodegenerative disease, chorea-acanthocytosis (ChAc), which is caused by mutations in the VPS13A gene—and for which about 1000 cases are estimated worldwide—and Charcot–Marie–Tooth neuropathy, a monogenic disorder caused by mutations in about 100 genes, are much less understood. Due to evolutionary conservation of basic cellular processes, a simple eukaryote, such as yeast, has often been used to investigate various neurodegenerative diseases, to study pathological processes, to identify targets suitable for drug treatment, and for the selection of effective drugs. Many of these findings have been further confirmed in higher cell models. We would like to dedicate this Special Issue of the International Journal of Molecular Sciences (MDPI), entitled “Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases”, to molecular aspects of basic and translational research on the most common, rare, and ultra-rare neurodegenerative diseases performed using yeasts. We invite you to submit to this Special Issue a review, mini-review, original research article, or short communication relevant to molecular mechanisms of neurodegenerative diseases. Research based on yeast model organisms, such as Saccharomyces cerevisiae, and nonconventional yeasts is welcome.

Prof. Dr. Teresa Zoladek
Dr. Joanna Kaminska
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. 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

  • yeast model organism
  • neurodegenerative diseases
  • Alzheimer’s disease
  • Parkinson’s disease
  • Huntington’s disease
  • rare and ultra-rare neurodegenerative diseases
  • molecular mechanisms of pathogenesis
  • drugs and drug targets

Published Papers (6 papers)

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Editorial

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3 pages, 195 KiB  
Editorial
Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0
by Joanna Kaminska and Teresa Zoladek
Int. J. Mol. Sci. 2022, 23(24), 15821; https://doi.org/10.3390/ijms232415821 - 13 Dec 2022
Cited by 1 | Viewed by 802
Abstract
One of the goals of human genetics is to discover the variants that contribute to human diseases [...] Full article
(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0)

Research

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17 pages, 2024 KiB  
Article
Validation of the Pathogenic Effect of IGHMBP2 Gene Mutations Based on Yeast S. cerevisiae Model
by Weronika Rzepnikowska, Joanna Kaminska and Andrzej Kochański
Int. J. Mol. Sci. 2022, 23(17), 9913; https://doi.org/10.3390/ijms23179913 - 31 Aug 2022
Cited by 3 | Viewed by 1420
Abstract
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a heritable neurodegenerative disease characterized by rapid respiratory failure within the first months of life and progressive muscle weakness and wasting. Although the causative gene, IGHMBP2, is well defined, information on IGHMBP2 [...] Read more.
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a heritable neurodegenerative disease characterized by rapid respiratory failure within the first months of life and progressive muscle weakness and wasting. Although the causative gene, IGHMBP2, is well defined, information on IGHMBP2 mutations is not always sufficient to diagnose particular patients, as the gene is highly polymorphic and the pathogenicity of many gene variants is unknown. In this study, we generated a simple yeast model to establish the significance of IGHMBP2 variants for disease development, especially those that are missense mutations. We have shown that cDNA of the human gene encodes protein which is functional in yeast cells and different pathogenic mutations affect this functionality. Furthermore, there is a correlation between the phenotype estimated in in vitro studies and our results, indicating that our model may be used to quickly and simply distinguish between pathogenic and non-pathogenic mutations identified in IGHMBP2 in patients. Full article
(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0)
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20 pages, 2986 KiB  
Article
The GTPase Arf1 Is a Determinant of Yeast Vps13 Localization to the Golgi Apparatus
by Damian Kolakowski, Weronika Rzepnikowska, Aneta Kaniak-Golik, Teresa Zoladek and Joanna Kaminska
Int. J. Mol. Sci. 2021, 22(22), 12274; https://doi.org/10.3390/ijms222212274 - 12 Nov 2021
Cited by 13 | Viewed by 2385
Abstract
VPS13 proteins are evolutionarily conserved. Mutations in the four human genes (VPS13A-D) encoding VPS13A-D proteins are linked to developmental or neurodegenerative diseases. The relationship between the specific localization of individual VPS13 proteins, their molecular functions, and the pathology of these diseases [...] Read more.
VPS13 proteins are evolutionarily conserved. Mutations in the four human genes (VPS13A-D) encoding VPS13A-D proteins are linked to developmental or neurodegenerative diseases. The relationship between the specific localization of individual VPS13 proteins, their molecular functions, and the pathology of these diseases is unknown. Here we used a yeast model to establish the determinants of Vps13′s interaction with the membranes of Golgi apparatus. We analyzed the different phenotypes of the arf1-3 arf2Δ vps13∆ strain, with reduced activity of the Arf1 GTPase, the master regulator of Golgi function and entirely devoid of Vps13. Our analysis led us to propose that Vps13 and Arf1 proteins cooperate at the Golgi apparatus. We showed that Vps13 binds to the Arf1 GTPase through its C-terminal Pleckstrin homology (PH)-like domain. This domain also interacts with phosphoinositol 4,5-bisphosphate as it was bound to liposomes enriched with this lipid. The homologous domain of VPS13A exhibited the same behavior. Furthermore, a fusion of the PH-like domain of Vps13 to green fluorescent protein was localized to Golgi structures in an Arf1-dependent manner. These results suggest that the PH-like domains and Arf1 are determinants of the localization of VPS13 proteins to the Golgi apparatus in yeast and humans. Full article
(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0)
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17 pages, 5182 KiB  
Article
Genetic Dissection of Vps13 Regulation in Yeast Using Disease Mutations from Human Orthologs
by Jae-Sook Park, Nancy M. Hollingsworth and Aaron M. Neiman
Int. J. Mol. Sci. 2021, 22(12), 6200; https://doi.org/10.3390/ijms22126200 - 08 Jun 2021
Cited by 6 | Viewed by 2489
Abstract
The VPS13 family of proteins have emerged as key players in intracellular lipid transport and human health. Humans have four different VPS13 orthologs, the dysfunction of which leads to different diseases. Yeast has a single VPS13 gene, which encodes a protein that localizes [...] Read more.
The VPS13 family of proteins have emerged as key players in intracellular lipid transport and human health. Humans have four different VPS13 orthologs, the dysfunction of which leads to different diseases. Yeast has a single VPS13 gene, which encodes a protein that localizes to multiple different membrane contact sites. The yeast vps13Δ mutant is pleiotropic, exhibiting defects in sporulation, protein trafficking, endoplasmic reticulum (ER)-phagy and mitochondrial function. Non-null alleles resulting from missense mutations can be useful reagents for understanding the multiple functions of a gene. The exceptionally large size of Vps13 makes the identification of key residues challenging. As a means to identify critical residues in yeast Vps13, amino acid substitution mutations from VPS13A, B, C and D, associated with human disease, were introduced at the cognate positions of yeast VPS13, some of which created separation-of-function alleles. Phenotypic analyses of these mutants have revealed that the promotion of ER-phagy is a fourth, genetically separable role of VPS13 and provide evidence that co-adaptors at the endosome mediate the activity of VPS13 in vacuolar sorting. Full article
(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0)
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Review

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24 pages, 1901 KiB  
Review
Yeast as a Model to Find New Drugs and Drug Targets for VPS13-Dependent Neurodegenerative Diseases
by Joanna Kaminska, Piotr Soczewka, Weronika Rzepnikowska and Teresa Zoladek
Int. J. Mol. Sci. 2022, 23(9), 5106; https://doi.org/10.3390/ijms23095106 - 04 May 2022
Cited by 7 | Viewed by 3050
Abstract
Mutations in human VPS13A-D genes result in rare neurological diseases, including chorea-acanthocytosis. The pathogenesis of these diseases is poorly understood, and no effective treatment is available. As VPS13 genes are evolutionarily conserved, the effects of the pathogenic mutations could be studied [...] Read more.
Mutations in human VPS13A-D genes result in rare neurological diseases, including chorea-acanthocytosis. The pathogenesis of these diseases is poorly understood, and no effective treatment is available. As VPS13 genes are evolutionarily conserved, the effects of the pathogenic mutations could be studied in model organisms, including yeast, where one VPS13 gene is present. In this review, we summarize advancements obtained using yeast. In recent studies, vps13Δ and vps13-I2749 yeast mutants, which are models of chorea-acanthocytosis, were used to screen for multicopy and chemical suppressors. Two of the suppressors, a fragment of the MYO3 and RCN2 genes, act by downregulating calcineurin activity. In addition, vps13Δ suppression was achieved by using calcineurin inhibitors. The other group of multicopy suppressors were genes: FET4, encoding iron transporter, and CTR1, CTR3 and CCC2, encoding copper transporters. Mechanisms of their suppression rely on causing an increase in the intracellular iron content. Moreover, among the identified chemical suppressors were copper ionophores, which require a functional iron uptake system for activity, and flavonoids, which bind iron. These findings point at areas for further investigation in a higher eukaryotic model of VPS13-related diseases and to new therapeutic targets: calcium signalling and copper and iron homeostasis. Furthermore, the identified drugs are interesting candidates for drug repurposing for these diseases. Full article
(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0)
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25 pages, 1088 KiB  
Review
α-Arrestins and Their Functions: From Yeast to Human Health
by Kacper Zbieralski and Donata Wawrzycka
Int. J. Mol. Sci. 2022, 23(9), 4988; https://doi.org/10.3390/ijms23094988 - 30 Apr 2022
Cited by 13 | Viewed by 3248
Abstract
α-Arrestins, also called arrestin-related trafficking adaptors (ARTs), constitute a large family of proteins conserved from yeast to humans. Despite their evolutionary precedence over their extensively studied relatives of the β-arrestin family, α-arrestins have been discovered relatively recently, and thus their properties are mostly [...] Read more.
α-Arrestins, also called arrestin-related trafficking adaptors (ARTs), constitute a large family of proteins conserved from yeast to humans. Despite their evolutionary precedence over their extensively studied relatives of the β-arrestin family, α-arrestins have been discovered relatively recently, and thus their properties are mostly unexplored. The predominant function of α-arrestins is the selective identification of membrane proteins for ubiquitination and degradation, which is an important element in maintaining membrane protein homeostasis as well as global cellular metabolisms. Among members of the arrestin clan, only α-arrestins possess PY motifs that allow canonical binding to WW domains of Rsp5/NEDD4 ubiquitin ligases and the subsequent ubiquitination of membrane proteins leading to their vacuolar/lysosomal degradation. The molecular mechanisms of the selective substrate’s targeting, function, and regulation of α-arrestins in response to different stimuli remain incompletely understood. Several functions of α-arrestins in animal models have been recently characterized, including redox homeostasis regulation, innate immune response regulation, and tumor suppression. However, the molecular mechanisms of α-arrestin regulation and substrate interactions are mainly based on observations from the yeast Saccharomyces cerevisiae model. Nonetheless, α-arrestins have been implicated in health disorders such as diabetes, cardiovascular diseases, neurodegenerative disorders, and tumor progression, placing them in the group of potential therapeutic targets. Full article
(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases 2.0)
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