Unknown

Dataset Information

0

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


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.

SUBMITTER: Yang Y 

PROVIDER: S-EPMC9304026 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC8792744 | biostudies-literature
| S-EPMC4794800 | biostudies-literature
| S-EPMC4027709 | biostudies-literature
| S-EPMC8577461 | biostudies-literature
| S-EPMC6541231 | biostudies-literature
| S-EPMC3660047 | biostudies-literature
| S-EPMC8648656 | biostudies-literature
| S-EPMC8521067 | biostudies-literature
| S-EPMC4614141 | biostudies-literature
| S-EPMC5217462 | biostudies-literature