Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy

• Published in: Cell death and differentiation Vol. 17; no. 10; pp. 1577 - 1587
• Main Authors: Nisoli, I, Chauvin, J P, Napoletano, F, Calamita, P, Zanin, V, Fanto, M, Charroux, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2010; Nature Publishing Group
• Subjects: 631/378/1689/364; 631/80/82/39; Animals; Apoptosis; Atrophy; Autophagy; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Disease; Disease Models, Animal; Drosophila; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Humans; Insects; Life Sciences; Medical prognosis; Mutation; Myoclonic Epilepsies, Progressive - genetics; Myoclonic Epilepsies, Progressive - pathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - toxicity; Neurobiology; Neurodegeneration; Neurodegenerative Diseases - pathology; Neuroglia - cytology; Neuroglia - drug effects; Neurons - cytology; Neurons - drug effects; Neurosciences; original-paper; Peptides - toxicity; Photoreceptors; Proteins; Stem Cells; Toxicity; Transcription Factors - genetics; Transcription Factors - metabolism; United Kingdom > UK; France; atrophin; neurodegeneration; autophagy; Neurodegeneration; Atrophin; Autophagy; Drosophila
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2010.31

Polyglutamine pathologies are neurodegenerative diseases that manifest both general polyglutamine toxicity and mutant protein-specific effects. Dentatorubral-pallidoluysian 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 analysed the mechanisms of cellular and organism toxicity. Our genetic and ultrastructural analysis of neurodegeneration suggests that autophagy may have a role in cellular degeneration when polyglutamine 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 autofluorescent pigments and proteinaceous residues usually degraded by the autophagy–lysosome system. Under these circumstances, further pharmacological and genetic induction of autophagy does not rescue neurodegeneration by polyglutamine 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.