The α7 neuronal nicotinic acetylcholine receptor (α7 nAChR) is a potential target for the development of Parkinson's disease (PD) therapeutics. α-Synuclein (α-Syn), a principal component of Lewy bodies (cytoplasmic inclusions), is a major contributor to PD pathophysiology. Previous studies have demonstrated that activating α7 nAChR protects against nigrostriatal dopamine degeneration in acute and chronic PD animal models induced by 6-hydroxydopamine and rotenone, respectively. In the present study, we investigated the effects of PNU282987, a selective α7 nAChR agonist, against α-Syn-induced neurotoxicity in α-SynWT-, α-SynA30P-, and α-SynE46K-N2a cells. PNU282987 exhibited substantial neuroprotection against both wild-type and mutant-type α-Syn-induced toxicity. Furthermore, PNU282987 promoted transcription factor EB activity and reduced intracellular α-Syn protein levels through autophagy induction. These results highlight the therapeutic potential of α7 nAChR activation in diseases characterized by α-Syn aggregation, such as PD.