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Edited by Anders Bj€orklund, Lund University, Lund, Sweden; received June 10, 2021; accepted April 20, 2022 Intraneuronal inclusions of misfolded a-synuclein (a-syn) and prion-like spread of the pathologic a-syn contribute to progressive neuronal death in Parkinson's disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting a-synucleinopathy has been developed. In this study, we provide evidence that astrocytes, especially those cultured from the ventral midbrain (VM), show therapeutic potential to alleviate a-syn pathology in multiple in vitro and in vivo a-synucleinopathic models. Regulation of neuronal a-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal a-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which a-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular a-syn aggregates. In addition to the aggregated form of a-syn, VM astrocytes reduced total a-syn protein loads both by actively scavenging extracellular a-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of a-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated a-syn pathology and protected the midbrain dopamine neurons from neurodegeneration. We further showed that cografting of VM astrocytes could be exploited in stem cell-based therapy for PD, in which host-to-graft transmission of a-syn pathology remains a critical concern for long-term cell therapeutic effects. [ABSTRACT FROM AUTHOR]