The fine line between waste disposal and recycling: DRPLA fly models illustrate the importance of completing the autophagy cycle for rescuing neurodegeneration.

Induction of autophagy protects from neurodegeneration in many proteinopathies and is being proposed as a therapeutic option. We generated Drosophila models for Dentatorubro-pallidoluysian Atrophy to dissect the mechanism of neuronal cell degeneration. These flies display severe lysosomal dysfunction caused by the Atrophin protein, as a distinctive feature that modulates polyglutamine toxicity. The autophagic flux is blocked after autophagosome-lysosome fusion, leading to clearance defects, and further induction of autophagy does not rescue neurodegeneration but is instead detrimental. This highlights the importance for the full cycle to be completed to achieve neuroprotection by autophagy, much like waste recycling, more than disposal, benefits society.