Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of aggregates (Lewy bodies) in neurons. ␣-Synuclein is the major protein in Lewy bodies and rare mutations in ␣-synuclein cause early-onset PD. Consequently, ␣-synuclein is implicated in the pathogenesis of PD. Here, we have investigated the degradation pathways of ␣-synuclein, using a stable inducible PC12 cell model, where the expression of exogenous human wild-type, A30P, or A53T ␣-synuclein can be switched on and off. We have used a panel of inhibitors/ stimulators of autophagy and proteasome function and followed ␣-synuclein degradation in these cells. We found that not only is ␣-synuclein degraded by the proteasome, but it is also degraded by autophagy. A role for autophagy was further supported by the presence of ␣-synuclein in organelles with the ultrastructural features of autophagic vesicles. Since rapamycin, a stimulator of autophagy, increased clearance of ␣-synuclein, it merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans.

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