Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy

Overview & Synopsis

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. Our data thus provide a crucial insight into the specific mechanism of a polyglutamine disease and reveal important differences in the role of autophagy with respect to other diseases of the same family.