Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson's disease

Abstract

Intraneuronal inclusions of misfolded alpha-synuclein (alpha-syn) and prion-like spread of the pathologic alpha-syn contribute to progressive neuronal death in Parkinson's disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting alpha-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 alpha-syn pathology in multiple in vitro and in vivo alpha-synucleinopathic models. Regulation of neuronal alpha-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal alpha-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which alpha-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular alpha-syn aggregates. In addition to the aggregated form of alpha-syn, VM astrocytes reduced total alpha-syn protein loads both by actively scavenging extracellular alpha-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of alpha-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated alpha-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 alpha-syn pathology remains a critical concern for long-term cell therapeutic effects.