Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat

Dulbecco Telethon Institute and Division of Neuroscience, DIBIT-San Raffaele Scientific Institute, Milan, Italy.
The EMBO Journal (Impact Factor: 10.43). 03/2011; 30(5):945-58. DOI: 10.1038/emboj.2011.1
Source: PubMed


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.

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Available from: Vera Giulia Volpi, Mar 14, 2015
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