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The benefits of humanized yeast models to study Parkinson's disease.

Franssens V, Bynens T, Van den Brande J, Vandermeeren K, Verduyckt M, Winderickx J - Oxid Med Cell Longev (2013)

Bottom Line: These so-called humanized yeast models for PD initially focused on α -synuclein, which plays a key role in the etiology of PD.More recently, a similar model to study the presumed pathobiology of the α -synuclein interaction partner synphilin-1 has been established.In this review we will discuss recent advances using these humanized yeast models, pointing to new roles for cell wall integrity signaling, Ca(2+) homeostasis, mitophagy, and the cytoskeleton.

View Article: PubMed Central - PubMed

Affiliation: Functional Biology, KU Leuven, Kasteelpark Arenberg 31, 3001 Heverlee, Belgium. vanessa.franssens@bio.kuleuven.be

ABSTRACT
Over the past decade, the baker's yeast Saccharomyces cerevisiae has proven to be a useful model system to investigate fundamental questions concerning the pathogenic role of human proteins in neurodegenerative diseases such as Parkinson's disease (PD). These so-called humanized yeast models for PD initially focused on α -synuclein, which plays a key role in the etiology of PD. Upon expression of this human protein in the baker's yeast Saccharomyces cerevisiae, the events leading to aggregation and the molecular mechanisms that result in cellular toxicity are faithfully reproduced. More recently, a similar model to study the presumed pathobiology of the α -synuclein interaction partner synphilin-1 has been established. In this review we will discuss recent advances using these humanized yeast models, pointing to new roles for cell wall integrity signaling, Ca(2+) homeostasis, mitophagy, and the cytoskeleton.

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Expression of α-synuclein and synphilin-1 in Saccharomyces cerevisiae. (a) Fluorescence microscopic visualization of wild type α-synuclein-eGFP (left panels) and dsRed-synphilin-1 (right panels) fusion proteins expressed separately in wild type yeast cells. (b) and (c) Quantification of viable cells (b) and DHE positive cells (c) in wild type yeast cells expressing wild type α-synuclein and synphilin-1 alone or together. The strains were kept in culture for two weeks [24].
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fig1: Expression of α-synuclein and synphilin-1 in Saccharomyces cerevisiae. (a) Fluorescence microscopic visualization of wild type α-synuclein-eGFP (left panels) and dsRed-synphilin-1 (right panels) fusion proteins expressed separately in wild type yeast cells. (b) and (c) Quantification of viable cells (b) and DHE positive cells (c) in wild type yeast cells expressing wild type α-synuclein and synphilin-1 alone or together. The strains were kept in culture for two weeks [24].

Mentions: It has already been a decade since yeast was used for the first time as a model to study α-synuclein toxicity [18]. In this study, the intracellular localization of wild type and mutant α-synuclein fused to green fluorescent protein was visualized in yeast cells. At low expression levels, the wild type and A53T mutant fusion proteins accumulate at the plasma membrane, consistent with the affinity of α-synuclein for phospholipids [19]. However, upon increased expression, their localization shifted from the plasma membrane towards cytoplasmic aggregates (Figure 1(a), left panel). This coincided with an increase in toxicity reflected in a reduced growth of the yeast cells expressing these human proteins. A30P mutant α-synuclein on the other hand displayed a cytosolic localization, and a minor toxic effect could only be seen upon multicopy expression. Since the description of this initial model, several other groups have taken advantage of the potential that the yeast model system offers to study PD-related features. Beside studies concentrating on a specific cell biological process, also genome-wide screens have been conducted to identify genes and processes that modulate α-synuclein-induced toxicity in yeast. These studies demonstrate that α-synuclein interferes with a broad range of processes to exert its toxicity, like membrane binding, protein quality control and autophagy, Ca2+ and Mn2+ transport, protein phosphorylation, vesicular trafficking and recycling, and cell death and aging [20–23].


The benefits of humanized yeast models to study Parkinson's disease.

Franssens V, Bynens T, Van den Brande J, Vandermeeren K, Verduyckt M, Winderickx J - Oxid Med Cell Longev (2013)

Expression of α-synuclein and synphilin-1 in Saccharomyces cerevisiae. (a) Fluorescence microscopic visualization of wild type α-synuclein-eGFP (left panels) and dsRed-synphilin-1 (right panels) fusion proteins expressed separately in wild type yeast cells. (b) and (c) Quantification of viable cells (b) and DHE positive cells (c) in wild type yeast cells expressing wild type α-synuclein and synphilin-1 alone or together. The strains were kept in culture for two weeks [24].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3713309&req=5

fig1: Expression of α-synuclein and synphilin-1 in Saccharomyces cerevisiae. (a) Fluorescence microscopic visualization of wild type α-synuclein-eGFP (left panels) and dsRed-synphilin-1 (right panels) fusion proteins expressed separately in wild type yeast cells. (b) and (c) Quantification of viable cells (b) and DHE positive cells (c) in wild type yeast cells expressing wild type α-synuclein and synphilin-1 alone or together. The strains were kept in culture for two weeks [24].
Mentions: It has already been a decade since yeast was used for the first time as a model to study α-synuclein toxicity [18]. In this study, the intracellular localization of wild type and mutant α-synuclein fused to green fluorescent protein was visualized in yeast cells. At low expression levels, the wild type and A53T mutant fusion proteins accumulate at the plasma membrane, consistent with the affinity of α-synuclein for phospholipids [19]. However, upon increased expression, their localization shifted from the plasma membrane towards cytoplasmic aggregates (Figure 1(a), left panel). This coincided with an increase in toxicity reflected in a reduced growth of the yeast cells expressing these human proteins. A30P mutant α-synuclein on the other hand displayed a cytosolic localization, and a minor toxic effect could only be seen upon multicopy expression. Since the description of this initial model, several other groups have taken advantage of the potential that the yeast model system offers to study PD-related features. Beside studies concentrating on a specific cell biological process, also genome-wide screens have been conducted to identify genes and processes that modulate α-synuclein-induced toxicity in yeast. These studies demonstrate that α-synuclein interferes with a broad range of processes to exert its toxicity, like membrane binding, protein quality control and autophagy, Ca2+ and Mn2+ transport, protein phosphorylation, vesicular trafficking and recycling, and cell death and aging [20–23].

Bottom Line: These so-called humanized yeast models for PD initially focused on α -synuclein, which plays a key role in the etiology of PD.More recently, a similar model to study the presumed pathobiology of the α -synuclein interaction partner synphilin-1 has been established.In this review we will discuss recent advances using these humanized yeast models, pointing to new roles for cell wall integrity signaling, Ca(2+) homeostasis, mitophagy, and the cytoskeleton.

View Article: PubMed Central - PubMed

Affiliation: Functional Biology, KU Leuven, Kasteelpark Arenberg 31, 3001 Heverlee, Belgium. vanessa.franssens@bio.kuleuven.be

ABSTRACT
Over the past decade, the baker's yeast Saccharomyces cerevisiae has proven to be a useful model system to investigate fundamental questions concerning the pathogenic role of human proteins in neurodegenerative diseases such as Parkinson's disease (PD). These so-called humanized yeast models for PD initially focused on α -synuclein, which plays a key role in the etiology of PD. Upon expression of this human protein in the baker's yeast Saccharomyces cerevisiae, the events leading to aggregation and the molecular mechanisms that result in cellular toxicity are faithfully reproduced. More recently, a similar model to study the presumed pathobiology of the α -synuclein interaction partner synphilin-1 has been established. In this review we will discuss recent advances using these humanized yeast models, pointing to new roles for cell wall integrity signaling, Ca(2+) homeostasis, mitophagy, and the cytoskeleton.

Show MeSH
Related in: MedlinePlus