송재진 (한양대학교, 현 Johns Hopkins University) | 한빛사논문 > 한빛사

한빛사논문

조회837

한양대학교, 현 Johns Hopkins University

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Proc. Natl. Acad. Sci. USA, July 15, 2022, 119 (29) e2110746119 | https://doi.org/10.1073/pnas.2110746119 Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson’s disease

Yunseon Yang^a,b,c,1, Jae-Jin Song^a,b,c,1, Yu Ree Choi^d,e, Seong-hoon Kim^a,b,c, Min-Jong Seok^a,b,c, Noviana Wulansari^a,b,c, Wahyu Handoko Wibowo Darsono^a,b,c, Oh-Chan Kwon^a,b,c, Mi-Yoon Chang^a,b, Sang Myun Park^d,e,2, and Sang-Hun Lee^a,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.

Abstract

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.

논문정보

형식Research article
게재일2022년 07월 (BRIC 등록일 2022-08-01)
연구진국내 연구진
분야 의약학 > 신경의학

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