Genome-Wide Screen for Modifiers of Ataxin-3 Neurodegeneration in Drosophila 英文参考文献.docVIP

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Genome-Wide Screen for Modifiers of Ataxin-3 Neurodegeneration in Drosophila 英文参考文献.doc

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Genome-Wide Screen for Modifiers of Ataxin-3 Neurodegeneration in Drosophila 英文参考文献

Genome-WideScreenforModifiers ofAtaxin-3NeurodegenerationinDrosophila Julide Bilen1¤,Nancy M.Bonini1,2* 1DepartmentofBiology,UniversityofPennsylvania,Philadelphia,Pennsylvania,UnitedStatesofAmerica,2HowardHughesMedicalInstitute,UniversityofPennsylvania, Philadelphia,Pennsylvania,UnitedStatesofAmerica Spinocerebellar ataxia type-3 (SCA3) is among the most common dominantly inherited ataxias, and is one of nine devastatinghumanneurodegenerativediseasescausedbytheexpansionofaCAGrepeatencodingglutaminewithin thegene.ThepolyglutaminedomainconferstoxicityontheproteinAtaxin-3leadingtoneuronaldysfunctionandloss. Although modifiers of polyglutamine toxicity have been identified, little is known concerning how the modifiers functionmechanisticallytoaffecttoxicity.Torevealinsightintospinocerebellarataxiatype-3,weperformedagenetic screen in Drosophila with pathogenic Ataxin-3-induced neurodegeneration and identified 25 modifiers defining 18 genes. Despite a variety of predicted molecular activities, biological analysis indicated that the modifiers affected protein misfolding. Detailed mechanistic studies revealed that some modifiers affected protein accumulation in a mannerdependentontheproteasome,whereasothersaffectedautophagy.SelectmodifiersofAtaxin-3alsoaffected tau, revealing common pathways between degeneration due to distinct human neurotoxic proteins. These findings providenewinsightintomolecularpathwaysofpolyQtoxicity,definingnoveltargetsforpromotingneuronalsurvival inhumanneurodegenerativedisease. Citation: Bilen J, Bonini NM (2007) Genome-wide screen for modifiers of Ataxin-3 neurodegeneration in Drosophila. PLoS Genet 3(10): e177. doi:10.1371/journal.pgen. 0030177 havebeenidenti?edusinganimalmodels,includingchaper- ones, transcriptional coregulators, and microRNAs [18–22]. Introduction Spinocerebellarataxiatype3(SCA3)isthemostcommon dominantly inherited ataxia worldwide and is caused by a CAGrepeatexpansionencodingglutaminewithintheATXN3 gene[1,2].Theexpandedpolygl