Genome-Wide Screen for Modifiers of Ataxin-3 Neurodegeneration in Drosophila

Bilen, Julide; Bonini, Nancy M.

doi:10.1371/journal.pgen.0030177

Cited by 189 publications

(205 citation statements)

References 65 publications

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“…To determine whether the observed protective effect of HSP67BC on polyQ aggregation could be extended to an in vivo setting, we employed the ataxin‐3 (SCA3) fly model (Bilen & Bonini, 2007). This fly model expresses the ataxin‐3 gene with 78 CAG repeats under the control of the UAS / gmr‐GAL4 expression system (Brand & Perrimon, 1993), resulting in eye‐specific expression.…”

Section: Resultsmentioning

confidence: 99%

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

et al. 2015

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SummaryDuring aging, oxidized, misfolded, and aggregated proteins accumulate in cells, while the capacity to deal with protein damage declines severely. To cope with the toxicity of damaged proteins, cells rely on protein quality control networks, in particular proteins belonging to the family of heat‐shock proteins (HSPs). As safeguards of the cellular proteome, HSPs assist in protein folding and prevent accumulation of damaged, misfolded proteins. Here, we compared the capacity of all Drosophila melanogaster small HSP family members for their ability to assist in refolding stress‐denatured substrates and/or to prevent aggregation of disease‐associated misfolded proteins. We identified CG14207 as a novel and potent small HSP member that exclusively assisted in HSP70‐dependent refolding of stress‐denatured proteins. Furthermore, we report that HSP67BC, which has no role in protein refolding, was the most effective small HSP preventing toxic protein aggregation in an HSP70‐independent manner. Importantly, overexpression of both CG14207 and HSP67BC in Drosophila leads to a mild increase in lifespan, demonstrating that increased levels of functionally diverse small HSPs can promote longevity in vivo.

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Section: Resultsmentioning

confidence: 99%

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

et al. 2015

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“…Drosophila was chosen because CSE is highly conserved between humans and flies (http://flybase.org/blast), and an established Drosophila model for SCA3 is available (27,28). In the fly model for SCA3, a truncated version of the pathogenic human ATXN3 gene containing a multiple CAG repeat is expressed, and key features of SCA3 disease are present (27)(28)(29). This model is suitable because the CAG repeat, and not the mutated protein, is considered to be the disease-causing entity in SCA3 and in several other polyQ diseases as well (29,30).…”

Section: Overexpression Of Cystathionine γ-Lyase Suppresses Detrimentmentioning

confidence: 99%

“…In the fly model for SCA3, a truncated version of the pathogenic human ATXN3 gene containing a multiple CAG repeat is expressed, and key features of SCA3 disease are present (27)(28)(29). This model is suitable because the CAG repeat, and not the mutated protein, is considered to be the disease-causing entity in SCA3 and in several other polyQ diseases as well (29,30). We used the Drosophila SCA3 model (also called SCA3 flies) to investigate the effects of CSE overexpression.…”

Section: Overexpression Of Cystathionine γ-Lyase Suppresses Detrimentmentioning

confidence: 99%

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Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Snijder

Baratashvili

Grzeschik

et al. 2015

Mol Med

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Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 (ATXN3) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a Drosophila model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of Drosophila cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies.

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“…Similarly, a screen for modifiers of mutant ataxin-1 toxicity identified components of the protein folding (dHDJ1) and clearance pathways (ubiquitin conjugases), as well as novel modifiers involved in RNA processing, transcriptional regulation, and cellular detoxification [91]. A genetic screen for modifiers of Drosophila eye degeneration induced by mutant ataxin-3 (ataxin-3tr Q78) identified 14 suppressors and one enhancer [92]. Analogous to the two studies described above [90,91], some suppressors belonged to the chaperone and ubiquitin-pathway component classes in addition to suppressor genes with roles in transcription, translation, and nuclear export.…”

Section: Genetic and Rnai Screensmentioning

confidence: 99%

Experimental Models for Identifying Modifiers of Polyglutamine-Induced Aggregation and Neurodegeneration

Calamini

Kaltenbach

2013

Neurotherapeutics

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Huntington's disease (HD) typifies a class of inherited neurodegenerative disorders in which a CAG expansion in a single gene leads to an extended polyglutamine tract and misfolding of the expressed protein, driving cumulative neural dysfunction and degeneration. HD is invariably fatal with symptoms that include progressive neuropsychiatric and cognitive impairments, and eventual motor disability. No curative therapies yet exist for HD and related polyglutamine diseases; therefore, substantial efforts have been made in the drug discovery field to identify potential drug and drug target candidates for disease-modifying treatment. In this context, we review here a range of early-stage screening approaches based in in vitro, cellular, and invertebrate models to identify pharmacological and genetic modifiers of polyglutamine aggregation and induced neurodegeneration. In addition, emerging technologies, including high-content analysis, threedimensional culture models, and induced pluripotent stem cells are increasingly being incorporated into drug discovery screening pipelines for protein misfolding disorders. Together, these diverse screening strategies are generating novel and exciting new probes for understanding the disease process and for furthering development of therapeutic candidates for eventual testing in the clinical setting.

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Genome-Wide Screen for Modifiers of Ataxin-3 Neurodegeneration in Drosophila

Cited by 189 publications

References 65 publications

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Experimental Models for Identifying Modifiers of Polyglutamine-Induced Aggregation and Neurodegeneration

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