Large-Scale Screen for Modifiers of Ataxin-3-Derived Polyglutamine-Induced Toxicity in Drosophila

Voßfeldt, Hannes; Butzlaff, Malte; Prüßing, Katja; Chárthaigh, Róisín-Ana Ní; Karsten, Peter; Lankes, Anne; Hamm, Sabine; Simons, Mikael; Adryan, Boris; Schulz, Jörg B.; Voigt, Aaron

doi:10.1371/journal.pone.0047452

Cited by 39 publications

(44 citation statements)

References 56 publications

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“…In the previous section we have presented a hypothesis that might explain why enhancers of polyQ-expanded ATXN1 toxicity and aggregation are enriched in CC domains. However, there have been several screens that tested the effect of gene silencing or overexpression on the aggregation and toxicity of polyQ proteins [25][26][27]. Are the obtained results consistent with our hypothesis?…”

Section: Enhancers Of Polyq Toxicity/aggregation and CC Contentsupporting

confidence: 75%

Aggregation of polyQ‐extended proteins is promoted by interaction with their natural coiled‐coil partners

et al. 2013

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Polyglutamine (polyQ) diseases are genetically inherited neurodegenerative disorders. They are caused by mutations that result in polyQ expansions of particular proteins. Mutant proteins form intranuclear aggregates, induce cytotoxicity and cause neuronal cell death. Protein interaction data suggest that polyQ regions modulate interactions between coiled-coil (CC) domains. In the case of the polyQ disease spinocerebellar ataxia type-1 (SCA1), interacting proteins with CC domains further enhance aggregation and toxicity of mutant ataxin-1 (ATXN1). Here, we suggest that CC partners interacting with the polyQ region of a mutant protein, increase its aggregation while partners that interact with a different region reduce the formation of aggregates. Computational analysis of genetic screens revealed that CC-rich proteins are highly enriched among genes that enhance pathogenicity of polyQ proteins, supporting our hypothesis. We therefore suggest that blocking interactions between mutant polyQ proteins and their CC partners might constitute a promising preventive strategy against neurodegeneration.

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Section: Enhancers Of Polyq Toxicity/aggregation and CC Contentsupporting

confidence: 75%

Aggregation of polyQ‐extended proteins is promoted by interaction with their natural coiled‐coil partners

et al. 2013

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“…Indeed, functional and/or physical interaction with polyglutamine proteins are also reported for several other shRNA target genes, such as Atf3 [59], Ddx6 [60], Fbxw8 [61], P2ry1 [62] and Map3k1 [63]. In addition, several shRNA targets found in this study are found as modifiers of toxicity in polyglutamine disease models, such as Trappc9 [34], Casp3 [64], Gnf1 ( Drosophila Rfc1) [65], and F40F8.1 ( C. elegans Cmpk1) [66]. Notably, gene expression array analysis using R6/2 HD model mice (T.Y and N.N.…”

Section: Discussionsupporting

confidence: 76%

Large-Scale RNA Interference Screening in Mammalian Cells Identifies Novel Regulators of Mutant Huntingtin Aggregation

et al. 2014

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In polyglutamine (polyQ) diseases including Huntington's disease (HD), mutant proteins containing expanded polyQ stretch form aggregates in neurons. Genetic or RNAi screenings in yeast, C. elegans or Drosophila have identified multiple genes modifying polyQ aggregation, a few of which are confirmed effective in mammals. However, the overall molecular mechanism underlying polyQ protein aggregation in mammalian cells still remains obscure. We here perform RNAi screening in mouse neuro2a cells to identify mammalian modifiers for aggregation of mutant huntingtin, a causative protein of HD. By systematic cell transfection and automated cell image analysis, we screen ∼12000 shRNA clones and identify 111 shRNAs that either suppress or enhance mutant huntingtin aggregation, without altering its gene expression. Classification of the shRNA-targets suggests that genes with various cellular functions such as gene transcription and protein phosphorylation are involved in modifying the aggregation. Subsequent analysis suggests that, in addition to the aggregation-modifiers sensitive to proteasome inhibition, some of them, such as a transcription factor Tcf20, and kinases Csnk1d and Pik3c2a, are insensitive to it. As for Tcf20, which contains polyQ stretches at N-terminus, its binding to mutant huntingtin aggregates is observed in neuro2a cells and in HD model mouse neurons. Notably, except Pik3c2a, the rest of the modifiers identified here are novel. Thus, our first large-scale RNAi screening in mammalian system identifies previously undescribed genetic players that regulate mutant huntingtin aggregation by several, possibly mammalian-specific mechanisms.

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“…The ataxia interactome that connects most of the known ataxia genes demonstrated that many ataxia-causing proteins share interacting partners, particularly among the transcription regulation, nuclear import, RNA splicing and ubiquitinylation processes [40]. These pathways have also been evidenced in genetic screens in SCA Drosophila models [178, 368-370]. The role of microRNA as potent phenotypic modulators has also been shown in fly models [92] and has been discussed in previous sections.…”

Section: Other Genetic Factorsmentioning

confidence: 99%

Consensus Paper: Pathological Mechanisms Underlying Neurodegeneration in Spinocerebellar Ataxias

et al. 2013

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Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice.

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Large-Scale Screen for Modifiers of Ataxin-3-Derived Polyglutamine-Induced Toxicity in Drosophila

Cited by 39 publications

References 56 publications

Aggregation of polyQ‐extended proteins is promoted by interaction with their natural coiled‐coil partners

Aggregation of polyQ‐extended proteins is promoted by interaction with their natural coiled‐coil partners

Large-Scale RNA Interference Screening in Mammalian Cells Identifies Novel Regulators of Mutant Huntingtin Aggregation

Consensus Paper: Pathological Mechanisms Underlying Neurodegeneration in Spinocerebellar Ataxias

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