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

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.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder with movement symptoms characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta of the midbrain with the concomitant loss of nigrostriatal DA neurotransmission. A pathologic hallmark of PD is intraneuronal inclusion of α-synuclein (α-syn) aggregates, called Lewy bodies and Lewy neurites. The α-syn aggregates cause various cellular dysfunctions including mitochondrial impairment, defective endoplasmic reticulum (ER) function, autolysosomal pathways, and synaptic and nuclear dysfunctions (1, 2). Aggregated α-syn is released from neuronal cells and acts as a ligand for patterned recognition receptors, which activate inflammatory responses in glial cells (3, 4). Furthermore, the pathologic protein aggregates undergo neuron-to-neuron transmission in a prion-like fashion (reviewed in ref. 5). The α-syn propagation and neuroinflammation are closely related to disease progression and clinical severity (6).Given its pathologic significance, the α-syn proteinopathy is a major research focus to develop disease-modifying therapies for PD and other synucleinopathic disorders such as Lewy body dementia, multiple system atrophy, and certain forms of Alzheimer’s disease. However, no therapeutic intervention to effectively eliminate the pathologic α-syn has been developed to date. In addition to the diseased conditions, the aggregated species of α-syn are also accumulated in the midbrain SN during normal aging, but not in young brain tissues (7), suggesting the existence of homeostatic regulation to prevent and resolve α-syn aggregation in young and healthy brains. This suggests homeostatic functions may be useful in developing therapeutic tools. In this regard, astrocytes are a prime cell type to be studied for therapeutic applications, as this glia cell type has multiple functions related to maintaining brain homeostasis, including those for correct functioning of neurons and protecting neuronal cells from pathologic insults (reviewed in ref. 8). Recent studies have shown the capacity of astrocytes to efficiently take up and degrade α-syn (9–12). Due to the astrocyte scavenging effect, α-syn inclusions are usually not detected in astrocytes of PD patients except in advanced stages of the disease (13–18). In addition, in contrast to efficient transmission of neuronal α-syn proteins into astrocytes, α-syn transfer from astrocytes to neuronal cells is inefficient (11), collectively suggesting a role for astrocytes in scavenging α-syn rather than in spreading it. The role of homeostatic astrocytes in α-syn pathology, however, remains to be unraveled.In this study, we showed that astrocytes, especially those cultured from the ventral midbrain (VM), the brain region primarily affected in PD, substantially alleviate neuronal α-syn pathology by regulating a series of the proteostasis procedures associated with formation, transmission, disaggregation, and clearance of toxic α-syn aggregates. Upon transplantation, VM-type astrocytes efficiently eliminated pathologic α-syn accumulation and α-syn–induced DA neuron degeneration in the midbrain of PD model mice. We further show that host-to-graft propagation of toxic α-syn, reported as a critical concern in the cell-based therapeutic approach for PD (19, 20), was greatly prevented by cografting the cultured astrocytes. Based on these findings, the therapeutic actions of astrocytes are proposed for use in relieving α-syn–mediated neuronal toxicity and in setting up a desirable cell-based therapy free from host-to-graft α-syn propagation in PD.