Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity

Yeger-Lotem, Esti; Riva, Laura; Su, Linhui Julie; Gitler, Aaron D.; Cashikar, Anil G.; King, Oliver D.; Auluck, Pavan K.; Geddie, Melissa L.; Valastyan, Julie S.; Karger, David R.; Lindquist, Susan; Fraenkel, Ernest

doi:10.1038/ng.337

Cited by 265 publications

(394 citation statements)

References 71 publications

(88 reference statements)

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“…Proteins that promote forward-vesicle trafficking (e.g., the Rab1 GTPase, Ypt1) suppress α-synuclein toxicity, whereas those that inhibit it (e.g., the Rab1 GTPase activating protein, Gyp8) enhance it (16). In an unbiased genomewide screen for modifiers of α-synuclein toxicity, we recovered Tpo4 as an enhancer of toxicity (21). Tpo4 is a member of a family of proteins responsible for polyamine transport in Saccharomyces cerevisiae (22).…”

Section: Yeast Studies Establish a Link Between Polyamines And α-Synumentioning

confidence: 99%

Polyamine pathway contributes to the pathogenesis of Parkinson disease

Lewandowski¹,

Verbitsky

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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133

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The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.functional MRI | SAT1 | brainstem

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Section: Yeast Studies Establish a Link Between Polyamines And α-Synumentioning

confidence: 99%

Polyamine pathway contributes to the pathogenesis of Parkinson disease

Lewandowski¹,

Verbitsky

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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133

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“…To investigate more thoroughly the mechanisms by which the splice isoforms induce toxicity, we tested all 77 genes that previously had been identified as suppressors or enhancers of α-synFL-induced toxicity (17,27). Each gene was tested at least three times against each splice isoform strain and against the full-length protein (Fig.…”

Section: α-Syn Splice Isoforms Show Differential Responses To Osh3mentioning

confidence: 99%

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Valastyan¹,

Termine²,

Lindquist³

2014

Proc. Natl. Acad. Sci. U.S.A.

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Synucleinopathies are neurodegenerative diseases associated with toxicity of the lipid-binding protein α-synuclein (α-syn). When expressed in yeast, α-syn associates with membranes at the endoplasmic reticulum and traffics with vesicles out to the plasma membrane. At higher levels it elicits a number of phenotypes, including blocking vesicle trafficking. The expression of α-syn splice isoforms varies with disease, but how these isoforms affect protein function is unknown. We investigated two of the most abundant isoforms, resulting in deletion of exon four (α-synΔ4) or exon six (α-synΔ6). α-SynΔ4, missing part of the lipid-binding domain, had reduced toxicity and membrane binding. α-SynΔ6, missing part of the protein-protein interaction domain, had reduced toxicity but no reduction in membrane binding. To compare the mechanism by which the splice isoforms exert toxicity, equally toxic strains were probed with genetic modifiers of α-syn-induced toxicity. Most modifiers equally altered the toxicity induced by the splice isoforms and full-length α-syn (α-synFL). However, the splice isoform strains responded differently to a sterol-binding protein, leading us to examine the effect of sterols on α-syn-induced toxicity. Upon inhibition of sterol synthesis, α-synFL and α-synΔ6, but not α-synΔ4, showed decreased plasma membrane association, increased vesicular association, and increased cellular toxicity. Thus, higher membrane sterol concentrations favor plasma membrane binding of α-synFL and α-synΔ6 and may be protective of synucleinopathy progression. Given the common use of cholesterol-reducing statins and these potential effects on membrane binding proteins, further investigation of how sterol concentration and α-syn splice isoforms affect vesicular trafficking in synucleinopathies is warranted.

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“…Likewise, multiple α-syn toxicity modifiers have been identified through yeast screens using the propensity of this single-celled eukaryote toward ER stress and cell death with the expression of α-syn [27]. Yeast YPK9 (a lysosomal ATPase) was identified in such a screen as a suppressor of α-syn toxicity.…”

Section: Usefulness Of C Elegans α-Synuclein Model For Analysis Of Nmentioning

confidence: 99%

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

Dexter

Caldwell

2012

Neurotherapeutics

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Summary Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases such as Parkinson's disease (PD) and dystonia. The use of animal model systems can provide links to susceptibility factors, as well as therapeutic interventions. In this regard, the nematode roundworm, Caenorhabditis elegans, is ideal for examining age-dependent neurodegenerative disease studies. It is genetically tractable, has a short lifespan, and a well-defined nervous system. Green fluorescent protein is readily visualized in C. elegans because it is a transparent organism, thus the nervous system and factors that alter the viability of neurons can be directly examined in vivo. Through expression of the human PD-associated protein (α-synuclein in the worm dopamine neurons), neurodegeneration is observed in an age-dependent manner. Furthermore, expression of the early-onset dystonia-related protein torsinA increases vulnerability to endoplasmic reticulum (ER) stress in C. elegans, because torsinA is located in the ER. Here we provide an overview of collaborative studies we have conducted that collectively demonstrate the usefulness of the nematode model to discern functional effectors of dopaminergic neurodegeneration and ER stress that translate to mammalian data in the fields of PD and dystonia. Taken together, the application of C.elegans toward the evaluation of genetic modifiers for movement disorders research has predictive value and serves to accelerate the path forward for therapeutic interventions.

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Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity

Cited by 265 publications

References 71 publications

Polyamine pathway contributes to the pathogenesis of Parkinson disease

Polyamine pathway contributes to the pathogenesis of Parkinson disease

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

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