TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
Abstract
This study shows that neurodegenerative changes induced by α-synuclein in midbrain dopamine neurons in vivo can be blocked through activation of the autophagy-lysosome pathway. Using an adeno-associated virus model of Parkinson disease to overexpress α-synuclein in the substantia nigra, we show that genetic [transcription factor EB (TFEB) and Beclin-1 overexpression] or pharmacological (rapalog) manipulations that enhance autophagy protect nigral neurons from α-synuclein toxicity, but inhibiting autophagy exacerbates α-synuclein toxicity. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and identify TFEB as a target for therapies aimed at neuroprotection and disease modification in Parkinson disease.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- May 2013
- DOI:
- 10.1073/pnas.1305623110
- Bibcode:
- 2013PNAS..110E1817D