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Citation
Bilen, J., Bonini, N.M. (2007). Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila.  PLoS Genet. 3(10): e177.
FlyBase ID
FBrf0202746
Publication Type
Research paper
Abstract

Spinocerebellar ataxia type-3 (SCA3) is among the most common dominantly inherited ataxias, and is one of nine devastating human neurodegenerative diseases caused by the expansion of a CAG repeat encoding glutamine within the gene. The polyglutamine domain confers toxicity on the protein Ataxin-3 leading to neuronal dysfunction and loss. Although modifiers of polyglutamine toxicity have been identified, little is known concerning how the modifiers function mechanistically to affect toxicity. To reveal insight into spinocerebellar ataxia type-3, we performed a genetic 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 manner dependent on the proteasome, whereas others affected autophagy. Select modifiers of Ataxin-3 also affected tau, revealing common pathways between degeneration due to distinct human neurotoxic proteins. These findings provide new insight into molecular pathways of polyQ toxicity, defining novel targets for promoting neuronal survival in human neurodegenerative disease.

PubMed ID
PubMed Central ID
PMC2041992 (PMC) (EuropePMC)
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Secondary IDs
  • FBrf0200965
Language of Publication
English
Additional Languages of Abstract
Parent Publication
Publication Type
Journal
Abbreviation
PLoS Genet.
Title
PLoS Genetics
Publication Year
2005-
ISBN/ISSN
1553-7404 1553-7390
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