Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson’s disease
| Autor: | Yunseon Yang, Jae-Jin Song, Yu Ree Choi, Seong-hoon Kim, Min-Jong Seok, Noviana Wulansari, Wahyu Handoko Wibowo Darsono, Oh-Chan Kwon, Mi-Yoon Chang, Sang Myun Park, Sang-Hun Lee |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 119 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2110746119 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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