title: Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat.
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.
authors.affiliation: Dulbecco Telethon Institute and Division of Neuroscience, DIBIT-San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Napoletano
authors.forename: Simona
authors.initials: S
authors.lastname: Occhi
authors.forename: Piera
authors.initials: P
authors.lastname: Calamita
authors.forename: Vera
authors.initials: V
authors.lastname: Volpi
authors.forename: Eric
authors.initials: E
authors.lastname: Blanc
authors.forename: Bernard
authors.initials: B
authors.lastname: Charroux
authors.forename: Julien
authors.initials: J
authors.lastname: Royet
authors.forename: Manolis
authors.initials: M
authors.lastname: Fanto
mesh_terms: D000818:Animals; D001343:Autophagy; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C095278:atrophin-1; C472307:ft protein, Drosophila; C097188:polyglutamine