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Two of the primary features of Parkinson's disease (PD) are the accumulation of α-synuclein (α-Syn) and the depletion of lysosomal-associated membrane protein 1 (LAMP1) in the brain. Beneficial effects of environmental enrichment (EE) have been reported on the activation of lysosomal function and the amelioration of PD symptoms. Furthermore, Reelin could be a novel therapeutic target in PD. Hence, in this study, we validated the effects of EE on the activation of LAMP1 via Reelin in PD. Heterogeneous α-Syn (A53T)-overexpressing transgenic mice (age 6 and 16 months) were exposed to EE for 8 weeks. After motor and cognitive tests, brain tissues were obtained from mice and subjected to immunohistochemistry and molecular analyses. EE ameliorated motor and non-motor symptoms, protected dopamine neurons, and reduced pathological α-Syn accumulation in the early stage of PD. Striatal Reelin levels were altered depending on the disease stage and regulated by EE in PD mice. To elucidate the underlying mechanism of the effect of EE on PD, we performed further molecular and cellular analyses using activated preformed fibril (PFF)-induced SH-SY5Y cells, an in vitro model of PD, which were treated with recombinant Reelin protein and a Reelin blocker, CR-50. The CR-50 increased pathological α-Syn accumulation and accelerated dopamine neuronal degeneration by decreasing LAMP1 in the PFF-induced PD model. Our results showed that Reelin increased LAMP1 after EE and decreased pathological α-Syn accumulation, thus protecting dopamine neurons from degeneration in the striatum and substantia nigra, and ameliorating neurobehavioral deficits. These results suggest that Reelin is a promising target in treating histopathological changes and improving behavioral symptoms associated with PD. • Reelin was known to be altered in patients with Parkinson's disease (PD). • Environmental enrichment (EE) increased Reelin with phenotypic improvement in PD. • Reelin restored by EE protected dopaminergic neurons in the early stage of PD. • Pathological α-Synuclein and LAMP1 were normalized by EE in the early stage of PD. • CR-50, a Reelin-neutralizing antibody validated the therapeutic effect of Reelin. [ABSTRACT FROM AUTHOR]