Abnormal neuronal aggregation of ␣-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive ␣-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial ␣-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that ␣-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of ␣-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human ␣-synuclein. Furthermore, astrocytes that were exposed to neuronal ␣-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of ␣-synuclein. Together, these results suggest that astroglial ␣-synuclein pathology is produced by direct transmission of neuronal ␣-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.

Abnormal aggregation of α-synuclein and sustained microglial activation are important contributors to the pathogenic processes in Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro, and in vivo approaches, we show that extracellular α-synuclein released from neuronal cells is an endogenous agonist for toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. TLR2 ligand activity of α-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric α-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.

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J. Neurochem. (2010) 113, 1263–1274. Abstract Parkinson’s disease is characterized by deposition of misfolded/aggregated α‐synuclein proteins in multiple regions of the brain. Neurons can release α‐synuclein; through this release, pathological forms of α‐synuclein are propagated between neurons, and also cause neuroinflammation. In this study, we demonstrate that release of α‐synuclein is consistently increased under various protein misfolding stress conditions in both neuroblastoma and primary neuron models. This release is mediated by a non‐classical, endoplasmic reticulum (ER)/Golgi‐independent exocytosis, and stress‐induced release coincides with increased translocation of α‐synuclein into vesicles. Both vesicle translocation and secretion were blocked by attachment of a highly stable, globular protein to α‐synuclein, whereas forced protein misfolding resulted in an increase in both of these activities. Mass spectrometry analysis showed a higher degree of oxidative modification in secreted α‐synuclein than in the cellular protein. Together, these results suggest that structurally abnormal, damaged α‐synuclein proteins translocate preferentially into vesicles and are released from neuronal cells via exocytosis.

Parkinson's disease (PD) is characterized by selective and progressive degeneration of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNpc) and by abnormal aggregation of α -synuclein. Previous studies have suggested that DA can interact with α -synuclein, thus modulating the aggregation process of this protein; this interaction may account for the selective vulnerability of DA neurons in patients with PD. However, the relationship between DA and α -synuclein, and the role in progressive degeneration of DA neurons remains elusive. We have shown that in the presence of DA, recombinant human α -synuclein produces non-fibrillar, SDS-resistant oligomers, while β-sheet-rich fibril formation is inhibited. Pharmacologic elevation of the cytoplasmic DA level increased the formation of SDS-resistant oligomers in DA-producing neuronal cells. DA promoted α -synuclein oligomerization in intracellular vesicles, but not in the cytosol. Furthermore, elevation of DA levels increased secretion of α-synuclein oligomers to the extracellular space, but the secretion of monomers was not changed. DA-induced secretion of α -synuclein oligomers may contribute to the progressive loss of the dopaminergic neuronal population and the pronounced neuroinflammation observed in the SNpc in patients with PD.

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