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EMBO J. 2011 Mar 2;30(5):945-58. doi: 10.1038/emboj.2011.1. Epub 2011 Jan 28.

Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat.

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  • 1Dulbecco Telethon Institute and Division of Neuroscience, DIBIT-San Raffaele Scientific Institute, Milan, Italy.

Abstract

Large alterations in transcription accompany neurodegeneration in polyglutamine (polyQ) diseases. These pathologies manifest both general polyQ toxicity and mutant protein-specific effects. In this study, we report that the fat tumour suppressor gene mediates neurodegeneration induced by the polyQ protein Atrophin. We have monitored early transcriptional alterations in a Drosophila model of Dentatorubral-pallidoluysian Atrophy and found that polyQ Atrophins downregulate fat. Fat protects from neurodegeneration and Atrophin toxicity through the Hippo kinase cascade. Fat/Hippo signalling does not provoke neurodegeneration by stimulating overgrowth; rather, it alters the autophagic flux in photoreceptor neurons, thereby affecting cell homeostasis. Our data thus provide a crucial insight into the specific mechanism of a polyQ disease and reveal an unexpected neuroprotective role of the Fat/Hippo pathway.

PMID:
21278706
[PubMed - indexed for MEDLINE]
PMCID:
PMC3049215
Free PMC Article

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