Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila.
Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila.
复制标题
DOI：
10.1371/journal.pgen.0030177
复制
发表时间：
2007-10
期刊：
影响因子：
4.5
通讯作者：
Bonini NM
中科院分区：
文献类型：
--
作者：
Bilen J;Bonini NM
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. Spinocerebellar ataxia type-3 is the most common dominantly inherited movement disorder and is caused by a CAG repeat expansion within the gene ATXN3, encoding the Ataxin-3 protein. This leads to a protein with an expanded polyglutamine domain, which confers a dominant toxicity on the protein, leading to late onset, progressive neural degeneration in the brain. Although some modifiers of Ataxin-3 toxicity have been defined, little was known about their molecular mechanisms of action. The fruit fly Drosophila recapitulates fundamental aspects of the human disease. Here, we performed a genome-wide screen for new modifiers of Ataxin-3 toxicity using the fly and defined 25 modifiers in 18 genes. The majority of the genes belong to chaperone and ubiquitin proteasome pathways, which modulate protein folding and degradation, but the remaining modifiers have a broad range of predicted molecular functions. Assays in vivo revealed that the biological activity of all modifiers converge on aiding in situations of protein misfolding, despite distinct predicted molecular functions. Select modifiers of Ataxin-3 toxicity also modulated tau toxicity associated with Alzheimer disease. These findings underscore the importance of protein homeostasis pathways to disease and provide the foundation for new therapeutic insight.
