International Journal of Molecular Sciences

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Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases

by Joanna Kaminska and Teresa Zoladek

Int. J. Mol. Sci. 2021, 22(16), 8775; https://doi.org/10.3390/ijms22168775 - 16 Aug 2021

Cited by 1 | Viewed by 1596

Abstract

Neurodegenerative diseases are a group of age-related diseases and a growing problem in an aging society [...] Full article

(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases)

Research

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27 pages, 7891 KiB

Open AccessArticle

eIF3a Destabilization and TDP-43 Alter Dynamics of Heat-Induced Stress Granules

by Ivana Malcova, Lenka Senohrabkova, Lenka Novakova and Jiri Hasek

Int. J. Mol. Sci. 2021, 22(10), 5164; https://doi.org/10.3390/ijms22105164 - 13 May 2021

Cited by 6 | Viewed by 2849

Abstract

Stress granules (SGs) are membrane-less assemblies arising upon various stresses in eukaryotic cells. They sequester mRNAs and proteins from stressful conditions and modulate gene expression to enable cells to resume translation and growth after stress relief. SGs containing the translation initiation factor eIF3a/Rpg1 [...] Read more.

Stress granules (SGs) are membrane-less assemblies arising upon various stresses in eukaryotic cells. They sequester mRNAs and proteins from stressful conditions and modulate gene expression to enable cells to resume translation and growth after stress relief. SGs containing the translation initiation factor eIF3a/Rpg1 arise in yeast cells upon robust heat shock (HS) at 46 °C only. We demonstrate that the destabilization of Rpg1 within the PCI domain in the Rpg1-3 variant leads to SGs assembly already at moderate HS at 42 °C. These are bona fide SGs arising upon translation arrest containing mRNAs, which are components of the translation machinery, and associating with P-bodies. HS SGs associate with endoplasmatic reticulum and mitochondria and their contact sites ERMES. Although Rpg1-3-labeled SGs arise at a lower temperature, their disassembly is delayed after HS at 46 °C. Remarkably, the delayed disassembly of HS SGs after the robust HS is reversed by TDP-43, which is a human protein connected with amyotrophic lateral sclerosis. TDP-43 colocalizes with HS SGs in yeast cells and facilitates cell regrowth after the stress relief. Based on our results, we propose yeast HS SGs labeled by Rpg1 and its variants as a novel model system to study functions of TDP-43 in stress granules disassembly. Full article

(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases)

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25 pages, 5905 KiB

Open AccessArticle

Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells, a Model of VPS13-Related Diseases

by Piotr Soczewka, Déborah Tribouillard-Tanvier, Jean-Paul di Rago, Teresa Zoladek and Joanna Kaminska

Int. J. Mol. Sci. 2021, 22(5), 2248; https://doi.org/10.3390/ijms22052248 - 24 Feb 2021

Cited by 6 | Viewed by 3537

Abstract

Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson’s diseases, respectively, and iron imbalance is observed in Parkinson’s and Alzheimer’s diseases. To better understand human diseases, Saccharomyces [...] Read more.

Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson’s diseases, respectively, and iron imbalance is observed in Parkinson’s and Alzheimer’s diseases. To better understand human diseases, Saccharomyces cerevisiae yeast are used as a model organism. In our studies, we used the vps13Δ yeast strain as a model of rare neurological diseases caused by mutations in VPS13A–D genes. In this work, we show that overexpression of genes encoding copper transporters, CTR1, CTR3, and CCC2, or the addition of copper salt to the medium, improved functioning of the vps13Δ mutant. We show that their mechanism of action, at least partially, depends on increasing iron content in the cells by the copper-dependent iron uptake system. Finally, we present that treatment with copper ionophores, disulfiram, elesclomol, and sodium pyrithione, also resulted in alleviation of the defects observed in vps13Δ cells. Our study points at copper and iron homeostasis as a potential therapeutic target for further investigation in higher eukaryotic models of VPS13-related diseases. Full article

(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases)

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18 pages, 3003 KiB

Open AccessArticle

Yeasts as Complementary Model Systems for the Study of the Pathological Repercussions of Enhanced Synphilin-1 Glycation and Oxidation

by David Seynnaeve, Daniel P. Mulvihill, Joris Winderickx and Vanessa Franssens

Int. J. Mol. Sci. 2021, 22(4), 1677; https://doi.org/10.3390/ijms22041677 - 7 Feb 2021

Cited by 1 | Viewed by 2429

Abstract

Synphilin-1 has previously been identified as an interaction partner of α-Synuclein (αSyn), a primary constituent of neurodegenerative disease-linked Lewy bodies. In this study, the repercussions of a disrupted glyoxalase system and aldose reductase function on Synphilin-1 inclusion formation characteristics and cell growth were [...] Read more.

Synphilin-1 has previously been identified as an interaction partner of α-Synuclein (αSyn), a primary constituent of neurodegenerative disease-linked Lewy bodies. In this study, the repercussions of a disrupted glyoxalase system and aldose reductase function on Synphilin-1 inclusion formation characteristics and cell growth were investigated. To this end, either fluorescent dsRed-tagged or non-tagged human SNCAIP, which encodes the Synphilin-1 protein, was expressed in Saccharomyces cerevisiae and Schizosaccharomyces pombe yeast strains devoid of enzymes Glo1, Glo2, and Gre3. Presented data shows that lack of Glo2 and Gre3 activity in S. cerevisiae increases the formation of large Synphilin-1 inclusions. This correlates with enhanced oxidative stress levels and an inhibitory effect on exponential growth, which is most likely caused by deregulation of autophagic degradation capacity, due to excessive Synphilin-1 aggresome build-up. These findings illustrate the detrimental impact of increased oxidation and glycation on Synphilin-1 inclusion formation. Similarly, polar-localised inclusions were observed in wild-type S. pombe cells and strains deleted for either glo1⁺ or glo2⁺. Contrary to S. cerevisiae, however, no growth defects were observed upon expression of SNCAIP. Altogether, our findings show the relevance of yeasts, especially S. cerevisiae, as complementary models to unravel mechanisms contributing to Synphilin-1 pathology in the context of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases)

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17 pages, 2827 KiB

Open AccessArticle

Partial Inhibition of Calcineurin Activity by Rcn2 as a Potential Remedy for Vps13 Deficiency

by Patrycja Wardaszka, Piotr Soczewka, Marzena Sienko, Teresa Zoladek and Joanna Kaminska

Int. J. Mol. Sci. 2021, 22(3), 1193; https://doi.org/10.3390/ijms22031193 - 26 Jan 2021

Cited by 4 | Viewed by 2662

Abstract

Regulation of calcineurin, a Ca²⁺/calmodulin-regulated phosphatase, is important for the nervous system, and its abnormal activity is associated with various pathologies, including neurodegenerative disorders. In yeast cells lacking the VPS13 gene (vps13Δ), a model of VPS13-linked neurological diseases, [...] Read more.

Regulation of calcineurin, a Ca²⁺/calmodulin-regulated phosphatase, is important for the nervous system, and its abnormal activity is associated with various pathologies, including neurodegenerative disorders. In yeast cells lacking the VPS13 gene (vps13Δ), a model of VPS13-linked neurological diseases, we recently demonstrated that calcineurin is activated, and its downregulation reduces the negative effects associated with vps13Δ mutation. Here, we show that overexpression of the RCN2 gene, which encodes a negative regulator of calcineurin, is beneficial for vps13Δ cells. We studied the molecular mechanism underlying this effect through site-directed mutagenesis of RCN2. The interaction of the resulting Rcn2 variants with a MAPK kinase, Slt2, and subunits of calcineurin was tested. We show that Rcn2 binds preferentially to Cmp2, one of two alternative catalytic subunits of calcineurin, and partially inhibits calcineurin. Rcn2 ability to bind to and reduce the activity of calcineurin was important for the suppression. The binding of Rcn2 to Cmp2 requires two motifs in Rcn2: the previously characterized C-terminal motif and a new N-terminal motif that was discovered in this study. Altogether, our findings can help to better understand calcineurin regulation and to develop new therapeutic strategies against neurodegenerative diseases based on modulation of the activity of selected calcineurin isoforms. Full article

(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases)

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16 pages, 2051 KiB

Open AccessArticle

Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene

by Xin Su, Alain Dautant, François Godard, Marine Bouhier, Teresa Zoladek, Roza Kucharczyk, Jean-Paul di Rago and Déborah Tribouillard-Tanvier

Int. J. Mol. Sci. 2020, 21(14), 5083; https://doi.org/10.3390/ijms21145083 - 18 Jul 2020

Cited by 11 | Viewed by 2595

Abstract

Probing the pathogenicity and functional consequences of mitochondrial DNA (mtDNA) mutations from patient’s cells and tissues is difficult due to genetic heteroplasmy (co-existence of wild type and mutated mtDNA in cells), occurrence of numerous mtDNA polymorphisms, and absence of methods for genetically transforming [...] Read more.

Probing the pathogenicity and functional consequences of mitochondrial DNA (mtDNA) mutations from patient’s cells and tissues is difficult due to genetic heteroplasmy (co-existence of wild type and mutated mtDNA in cells), occurrence of numerous mtDNA polymorphisms, and absence of methods for genetically transforming human mitochondria. Owing to its good fermenting capacity that enables survival to loss-of-function mtDNA mutations, its amenability to mitochondrial genome manipulation, and lack of heteroplasmy, Saccharomyces cerevisiae is an excellent model for studying and resolving the molecular bases of human diseases linked to mtDNA in a controlled genetic background. Using this model, we previously showed that a pathogenic mutation in mitochondrial ATP6 gene (m.9191T>C), that converts a highly conserved leucine residue into proline in human ATP synthase subunit a (aL222P), severely compromises the assembly of yeast ATP synthase and reduces by 90% the rate of mitochondrial ATP synthesis. Herein, we report the isolation of intragenic suppressors of this mutation. In light of recently described high resolution structures of ATP synthase, the results indicate that the m.9191T>C mutation disrupts a four α-helix bundle in subunit a and that the leucine residue it targets indirectly optimizes proton conduction through the membrane domain of ATP synthase. Full article

(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases)

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Review

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16 pages, 1647 KiB

Open AccessReview

The Vps13 Family of Lipid Transporters and Its Role at Membrane Contact Sites

by Samantha Katarzyna Dziurdzik and Elizabeth Conibear

Int. J. Mol. Sci. 2021, 22(6), 2905; https://doi.org/10.3390/ijms22062905 - 12 Mar 2021

Cited by 65 | Viewed by 5889

Abstract

The conserved VPS13 proteins constitute a new family of lipid transporters at membrane contact sites. These large proteins are suspected to bridge membranes and form a direct channel for lipid transport between organelles. Mutations in the 4 human homologs (VPS13A–D) are [...] Read more.

The conserved VPS13 proteins constitute a new family of lipid transporters at membrane contact sites. These large proteins are suspected to bridge membranes and form a direct channel for lipid transport between organelles. Mutations in the 4 human homologs (VPS13A–D) are associated with a number of neurological disorders, but little is known about their precise functions or the relevant contact sites affected in disease. In contrast, yeast has a single Vps13 protein which is recruited to multiple organelles and contact sites. The yeast model system has proved useful for studying the function of Vps13 at different organelles and identifying the localization determinants responsible for its membrane targeting. In this review we describe recent advances in our understanding of VPS13 proteins with a focus on yeast research. Full article

(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases)

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24 pages, 1629 KiB

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A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

by Weronika Rzepnikowska, Joanna Kaminska, Dagmara Kabzińska, Katarzyna Binięda and Andrzej Kochański

Int. J. Mol. Sci. 2020, 21(12), 4277; https://doi.org/10.3390/ijms21124277 - 16 Jun 2020

Cited by 9 | Viewed by 3491

Abstract

Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most [...] Read more.

Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease. Full article

(This article belongs to the Special Issue Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases)

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