Yunseon Yanga,b,c,1, Jae-Jin Songa,b,c,1, Yu Ree Choid,e, Seong-hoon Kima,b,c, Min-Jong Seoka,b,c, Noviana Wulansaria,b,c, Wahyu Handoko Wibowo Darsonoa,b,c, Oh-Chan Kwona,b,c, Mi-Yoon Changa,b, Sang Myun Parkd,e,2, and Sang-Hun Leea,b,c,2
aDepartment of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Korea; bHanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea; cGraduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea; dDepartment of Pharmacology, Ajou University School of Medicine, Suwon 16499, Korea; and eCenter for Convergence Research of Neurological Disorders, Ajou University School of Medicine, Suwon 16499, Korea
1Y.Y. and J.-J.S. contributed equally to this work.
2To whom correspondence may be addressed.
Intraneuronal inclusions of misfolded α-synuclein (α-syn) and prion-like spread of the pathologic α-syn contribute to progressive neuronal death in Parkinson’s disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting α-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 α-syn pathology in multiple in vitro and in vivo α-synucleinopathic models. Regulation of neuronal α-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal α-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which α-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular α-syn aggregates. In addition to the aggregated form of α-syn, VM astrocytes reduced total α-syn protein loads both by actively scavenging extracellular α-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of α-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated α-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 α-syn pathology remains a critical concern for long-term cell therapeutic effects.