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Updated: Jun 4, 2026
Mass Histology to Quantify Neurodegeneration in Drosophila
Published on: December 15, 2016
Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat
Francesco Napoletano1, Simona Occhi, Piera Calamita
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.
Insights
The fat gene protects against neurodegeneration in polyglutamine (polyQ) diseases by regulating the Hippo pathway. This pathway alters autophagic flux, offering a novel therapeutic target for neurodegenerative disorders.
Area of Science:
- Neurobiology
- Genetics
- Molecular Biology
Background:
- Neurodegeneration in polyglutamine (polyQ) diseases involves significant transcriptional changes.
- Both general polyQ toxicity and specific mutant protein effects contribute to these pathologies.
Purpose of the Study:
- To investigate the role of the fat tumor suppressor gene in polyQ-induced neurodegeneration.
- To identify early transcriptional alterations in a Drosophila model of Dentatorubral-pallidoluysian Atrophy (DRPLA).
Main Methods:
- Monitoring transcriptional alterations in a Drosophila model of DRPLA.
- Investigating the function of the fat gene and Hippo kinase cascade in neurodegeneration.
Main Results:
- PolyQ Atrophins downregulate the fat gene in Drosophila models.
- Fat/Hippo signaling protects against Atrophin-induced neurodegeneration.
- Fat/Hippo pathway alters autophagic flux in photoreceptor neurons, impacting cell homeostasis.
Conclusions:
- The fat tumor suppressor gene plays a critical role in mediating neurodegeneration caused by the polyQ protein Atrophin.
- The Fat/Hippo pathway exhibits unexpected neuroprotective functions in polyQ diseases by modulating autophagic flux, not overgrowth.
- These findings offer new insights into the mechanisms of polyQ diseases and suggest potential therapeutic strategies targeting the Fat/Hippo pathway.
