Abstract
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.
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Abbreviations
- DRPLA:
-
Dentatorubral-pallidoluysian Atrophy
- polyQ:
-
polyglutamine
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Acknowledgements
We thank Gabriele Schilling, David Borchelt, Helen McNeill, Joe Bateman, Tor Erik Rusten, Serge Birman, Thomas Neufeld, the DHSB, DGRC and Bloomington for reagents and stocks; Julien Royet, Sharon Tooze and Ana Cuervo for discussions; Aïcha Ouane for technical assistance; and Joy Burchell and Steve Catchpole for help with the phosphoimager. MF is supported by the Italian Telethon Foundation with a career development award and is an Assistant Telethon Scientist. This work was also supported by the European Union Marie Curie European Reintegration Grant 505739, by Fondazione Cariplo and Compagnia di San Paolo grants to MF, and funds from the Centre National de la Recherche Scientifique to BC and the KCL School of Biomedical and Health Sciences to MF.
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Nisoli, I., Chauvin, J., Napoletano, F. et al. Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy. Cell Death Differ 17, 1577–1587 (2010). https://doi.org/10.1038/cdd.2010.31
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DOI: https://doi.org/10.1038/cdd.2010.31
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