Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat.

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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 .