α-Synuclein is degraded by both autophagy and the proteasome. Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the formation of Lewy bodies, which contain α-synuclein. Mutations in α-synuclein cause early-onset PD, suggesting its role in PD pathogenesis. This study investigated α-synuclein degradation pathways using a stable inducible PC12 cell model. α-Synuclein was found to be degraded by both the proteasome and autophagy. Autophagy was further supported by the presence of α-synuclein in autophagic vesicles. Rapamycin, which stimulates autophagy, increased α-synuclein clearance, suggesting its potential as a therapeutic for PD. α-Synuclein is an aggregate-prone protein, and its degradation by autophagy was tested. Previous data suggested that aggregate-prone proteins are more likely to be cleared by autophagy than soluble proteins. In this study, α-synuclein was degraded by both proteasome and autophagy pathways. Proteasome inhibitors like epoxomicin and lactacystin increased α-synuclein levels, while autophagy inhibitors like 3-MA and bafilomycin A1 also increased α-synuclein levels, particularly in A53T mutants. Rapamycin, which stimulates autophagy, increased α-synuclein clearance in all mutants. α-Synuclein was observed inside vesicles with autophagic morphology, and immunogold electron microscopy confirmed its presence in autophagic vesicles. Confocal immunofluorescence showed α-synuclein localized inside acidic vacuoles labeled with LysoTracker Red. These findings support the role of the autophagy-lysosome pathway in α-synuclein degradation. The study suggests that aggregated α-synuclein is preferentially cleared by autophagy, while soluble forms are degraded by the proteasome. Rapamycin, which stimulates autophagy, may have therapeutic potential for PD due to its long-term use in humans.α-Synuclein is degraded by both autophagy and the proteasome. Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the formation of Lewy bodies, which contain α-synuclein. Mutations in α-synuclein cause early-onset PD, suggesting its role in PD pathogenesis. This study investigated α-synuclein degradation pathways using a stable inducible PC12 cell model. α-Synuclein was found to be degraded by both the proteasome and autophagy. Autophagy was further supported by the presence of α-synuclein in autophagic vesicles. Rapamycin, which stimulates autophagy, increased α-synuclein clearance, suggesting its potential as a therapeutic for PD. α-Synuclein is an aggregate-prone protein, and its degradation by autophagy was tested. Previous data suggested that aggregate-prone proteins are more likely to be cleared by autophagy than soluble proteins. In this study, α-synuclein was degraded by both proteasome and autophagy pathways. Proteasome inhibitors like epoxomicin and lactacystin increased α-synuclein levels, while autophagy inhibitors like 3-MA and bafilomycin A1 also increased α-synuclein levels, particularly in A53T mutants. Rapamycin, which stimulates autophagy, increased α-synuclein clearance in all mutants. α-Synuclein was observed inside vesicles with autophagic morphology, and immunogold electron microscopy confirmed its presence in autophagic vesicles. Confocal immunofluorescence showed α-synuclein localized inside acidic vacuoles labeled with LysoTracker Red. These findings support the role of the autophagy-lysosome pathway in α-synuclein degradation. The study suggests that aggregated α-synuclein is preferentially cleared by autophagy, while soluble forms are degraded by the proteasome. Rapamycin, which stimulates autophagy, may have therapeutic potential for PD due to its long-term use in humans.