Heat Shock Prevents Alpha-synuclein-induced Apoptosis in a Yeast Model of Parkinson's Disease

Flower, Todd R.; Chesnokova, Liudmila S.; Froelich, C.A.; Dixon, Cheryl; Witt, Stephan N.

doi:10.1016/j.jmb.2005.06.060

Cited by 218 publications

(192 citation statements)

References 73 publications

(84 reference statements)

Supporting

Mentioning

174

Contrasting

Unclassified

Order By: Relevance

“…Of note, acetic acid does not induce apoptosis in respiratory deficient (rho 0 ) cells and cell death is at least partially inhibited in cells that are unable to synthesize cytochrome c [21]. Several other studies have linked cytochrome c release, ROS formation, and changes in mitochondrial membrane potential to yeast apoptosis, such as heterologous expression of human Bax [24,25] or human α-synuclein [26], and deletion of the histone chaperone ASF1/CIA1 [27].…”

Section: Drug-induced Cell Deathmentioning

confidence: 99%

“…In yeast, mitochondrial respiration was shown to contribute to ROS generation and cell death during ER stress caused by defects of the UPR, as deletion of mitochondrial DNA inhibits the apoptotic phenotype [115]. In a yeast model of Parkinson's disease, heterologous expression of human α-synuclein triggers apoptotic cell death accompanied by the release of cytochrome c [26]. Application of a brief heat shock or overexpression of the Hsp70 protein Ssa3p were found to be preventive for α-synuclein toxicity [26], pointing to a critical role of the heat shock response during neurodegenerative disorders.…”

Section: Mitochondria Controlled Yeast Apoptosis Elucidates Neurodegementioning

confidence: 99%

“…In a yeast model of Parkinson's disease, heterologous expression of human α-synuclein triggers apoptotic cell death accompanied by the release of cytochrome c [26]. Application of a brief heat shock or overexpression of the Hsp70 protein Ssa3p were found to be preventive for α-synuclein toxicity [26], pointing to a critical role of the heat shock response during neurodegenerative disorders. Recently, it has been demonstrated that α-synuclein alters proteasome composition and impairs proteasome-mediated protein degradation, protein synthesis, and the ability to maintain survival during yeast stationary phase [116].…”

Section: Mitochondria Controlled Yeast Apoptosis Elucidates Neurodegementioning

confidence: 99%

See 2 more Smart Citations

The mitochondrial pathway in yeast apoptosis

et al. 2007

View full text Add to dashboard Cite

Mitochondria are not only important for the energetic status of the cell, but are also the fatal organelles deciding about cellular life and death. Complex mitochondrial features decisive for cell death execution in mammals are present and functional in yeast: AIF and cytochrome c release to the cytosol, mitochondrial fragmentation as well as mitochondrial hyperpolarisation followed by an oxidative burst, and breakdown of mitochondrial membrane potential. The easy accessibility of mitochondrial manipulations such as repression of respiration by growing yeast on glucose or deletion of mitochondrial DNA (rho 0 ) on the one hand and the unique ability of yeast cells to grow on nonfermentable carbon sources by switching on mitochondrial respiration on the other hand have made yeast an excellent tool to delineate the necessity for mitochondria in cell death execution. Yeast research indicates that the connection between mitochondria and apoptosis is intricate, as abrogation of mitochondrial function can be either deleterious or beneficial for the cell depending on the specific context of the death scenario. Surprisingly, mitochondrion dependent yeast apoptosis currently helps to understand the aetiology (or the complex biology) of lethal cytoskeletal alterations, ageing and neurodegeneration. For example, mutation of mitochondrial superoxide dismutase or CDC48/VCP mutations, both T. Eisenberg · S. Büttner · F. Madeo ( ) Institute of Molecular Biosciences, Universitaetsplatz 2, University of Graz, 8010 Graz, Austria e-mail: frank.madeo@uni-graz.at G. Kroemer Apoptosis, Cancer, and Immunity Unit, Institut Gustave Roussy, Faculté Paris Sud-Université, Institut National de la Santé et de la Recherche Médicale, Paris XI, France implicated in several neurodegenerative disorders, are associated with mitochondrial impairment and apoptosis in yeast.

show abstract

Section: Drug-induced Cell Deathmentioning

confidence: 99%

Section: Mitochondria Controlled Yeast Apoptosis Elucidates Neurodegementioning

confidence: 99%

Section: Mitochondria Controlled Yeast Apoptosis Elucidates Neurodegementioning

confidence: 99%

See 1 more Smart Citation

The mitochondrial pathway in yeast apoptosis

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Transformed yeast were grown overnight in minimal media containing glucose, diluted into fresh minimal media containing galactose and grown for 2 h (1-2 · 10 6 cells/ml) and treated with different [11,17]. At least three independent experiments were performed for all these assays.…”

Section: Viability and Growth Assaysmentioning

confidence: 99%

Transmembrane protein 85 from both human (TMEM85) and yeast (YGL231c) inhibit hydrogen peroxide mediated cell death in yeast

et al. 2008

View full text Add to dashboard Cite

Anti-apoptotic proteins are involved in modulating the process of apoptosis. Here, we report the identification of the previously uncharacterized transmembrane domain protein 85 (TMEM85) as a novel anti-apoptotic sequence. Using growth and viability assays, we demonstrate that the heterologous expression of human TMEM85 in yeast promotes growth and prevents cell death in response to oxidative stress. Overexpression of the yeast TMEM85 ortholog (YGL231c) also leads to increased resistance to oxidative stress. Analysis of the existing TMEM85 DNA complimentary to mRNAs revealed that the human TMEM85 gene is alternatively spliced to produce multiple transcripts and proteins. Thus TMEM85 is a complex gene that encodes a novel conserved anti-apoptotic protein.

show abstract

“…Recent studies have demonstrated that overexpressed ␣-syn in Saccharomyces cerevisiae localizes to the plasma membrane and forms inclusions (Outeiro and Lindquist, This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-08 -0827) on January 9, 2008. 2003; Flower et al, 2005). Expression of ␣-syn in yeast also was shown to inhibit growth, induce accumulation of lipid droplets, alter vesicle trafficking (Outeiro and Lindquist, 2003), increase reactive oxygen species (Flower et al, 2005), and stimulate the heat shock response . Furthermore, proteins involved in endoplasmic reticulum (ER)-to-Golgi trafficking may be involved in this ␣-syninduced growth defect because this defect was rescued by overexpressing Ypt1p, a Rab guanosine triphosphatase (GTPase; Cooper et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein–induced Aggregation of Cytoplasmic Vesicles inSaccharomyces cerevisiae

Soper¹,

Roy²,

Stieber³

et al. 2008

MBoC

146

168

View full text Add to dashboard Cite

Aggregated ␣-synuclein (␣-syn) fibrils form Lewy bodies (LBs), the signature lesions of Parkinson's disease (PD) and related synucleinopathies, but the pathogenesis and neurodegenerative effects of LBs remain enigmatic. Recent studies have shown that when overexpressed in Saccharomyces cerevisiae, ␣-syn localizes to plasma membranes and forms cytoplasmic accumulations similar to human ␣-syn inclusions. However, the exact nature, composition, temporal evolution, and underlying mechanisms of yeast ␣-syn accumulations and their relevance to human synucleinopathies are unknown. Here we provide ultrastructural evidence that ␣-syn accumulations are not comprised of LB-like fibrils, but are associated with clusters of vesicles. Live-cell imaging showed ␣-syn initially localized to the plasma membrane and subsequently formed accumulations in association with vesicles. Imaging of truncated and mutant forms of ␣-syn revealed the molecular determinants and vesicular trafficking pathways underlying this pathological process. Because vesicular clustering is also found in LB-containing neurons of PD brains, ␣-syn-mediated vesicular accumulation in yeast represents a model system to study specific aspects of neurodegeneration in PD and related synucleinopathies. INTRODUCTIONParkinson's disease (PD) is the most prevalent neurodegenerative movement disorder and is characterized by bradykinesia, rigidity, postural instability, and resting tremor (Galvin et al., 2001;Forman et al., 2005), as well as by the loss of dopaminergic neurons and presence of neuronal inclusions, known as Lewy bodies (LBs) and Lewy neurites (Forman et al., 2005). The identification of an ␣-syn gene (SNCA) mutation associated with autosomal dominant PD (Polymeropoulos et al., 1997), and the identification of fibrillar ␣-syn as the principal component of LB pathology (Spillantini et al., 1997), indicate that the LBs formed by ␣-syn define classic PD and are implicated in disease pathogenesis. The subsequent identification of additional disease-linked SNCA mutations (Polymeropoulos et al., 1997;Kruger et al., 1998;Zarranz et al., 2004), as well as replications of the SNCA gene (Singleton et al., 2003;Chartier-Harlin et al., 2004), indicate that both mutant ␣-syn and increased expression of wildtype (WT) ␣-syn can cause neurodegeneration.In addition to PD, filamentous ␣-syn inclusions have been detected in other neurodegenerative diseases including the LB variant of Alzheimer's disease, dementia with LBs, neurodegeneration with brain iron accumulation type-1, and multiple system atrophy, which are collectively known as synucleinopathies (Spillantini et al., 1997;Duda et al., 2000). ␣-syn fibrils exhibit properties of amyloid (Spillantini et al., 1998), and ␣-syn assembles into amyloid fibrils in vitro (Han et al., 1995;Giasson et al., 1999), whereas SNCA mutations can accelerate ␣-syn fibrillization (Conway et al., 1998;Greenbaum et al., 2005). Therefore, it is plausible that ␣-syn misfolds and aggregates into amyloid fibrils that are neurotoxic and play a cau...

show abstract

Heat Shock Prevents Alpha-synuclein-induced Apoptosis in a Yeast Model of Parkinson's Disease

Cited by 218 publications

References 73 publications

The mitochondrial pathway in yeast apoptosis

The mitochondrial pathway in yeast apoptosis

Transmembrane protein 85 from both human (TMEM85) and yeast (YGL231c) inhibit hydrogen peroxide mediated cell death in yeast

α-Synuclein–induced Aggregation of Cytoplasmic Vesicles inSaccharomyces cerevisiae

Contact Info

Product

Resources

About