Proceedings of The Physiological Society

King's College London (2011) Proc Physiol Soc 22, C11

Oral Communications

Polyglutamine Atrophin provokes autophagic neurodegeneration by repressing fat

M. Fanto1,2, S. Occhi2, V. Volpi1, I. Nisoli2, F. Napoletano2, P. Calamita1

1. MRC Centre Developmental Neurobiology, King's College London, London, United Kingdom. 2. Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.


Polyglutamine pathologies are neurodegenerative diseases that manifest both general polyglutamine toxicity and mutant protein specific effects. Dentatorubropallidoluysian Atrophy (DRPLA) is one of these disorders caused by mutations in the Atrophin-1 protein. We have generated several models for DRPLA in Drosophila and have analysed the mechanisms of cellular and organism toxicity. Our genetic and ultrastructural analysis of neurodegeneration suggests may play a role in cellular degeneration when polyQ proteins are overexpressed in neuronal and glial cells. Clearance of autophagic organelles is blocked at the lysosomal level after correct fusion between autophagosomes and lysosomes. This leads to accumulation of autofluorecent pigments and of proteinaceous residues usually degraded by the autophagy-lysosome system. In these circumstances, further pharmacological and genetic induction of autophagy does not rescue neurodegeneration by polyQ Atrophins, in contrast to many other neurodegenerative conditions. Large alterations in transcription also accompany neurodegeneration in polyglutamine diseases. We report that the fat tumour suppressor gene mediates neurodegeneration induced by the polyglutamine protein Atrophin. We have monitored early transcriptional alterations in a Drosophila model of Dentatorubral-pallidoluysian Atrophy and found that polyglutamine Atrophins downregulate fat. Fat protects from neurodegeneration and Atrophin toxicity through the Hippo kinase cascade. The 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 polyglutamine disease and reveal an unexpected neuroprotective role of the Fat/Hippo pathway.

Where applicable, experiments conform with Society ethical requirements