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Extracellular Interactions of Alpha-Synuclein in Multiple System Atrophy


Extracellular Interactions of Alpha-Synuclein in Multiple System Atrophy

Dario Valdinocci et al. Int J Mol Sci.


Multiple system atrophy, characterized by atypical Parkinsonism, results from central nervous system (CNS) cell loss and dysfunction linked to aggregates of the normally pre-synaptic α-synuclein protein. Mostly cytoplasmic pathological α-synuclein inclusion bodies occur predominantly in oligodendrocytes in affected brain regions and there is evidence that α-synuclein released by neurons is taken up preferentially by oligodendrocytes. However, extracellular α-synuclein has also been shown to interact with other neural cell types, including astrocytes and microglia, as well as extracellular factors, mediating neuroinflammation, cell-to-cell spread and other aspects of pathogenesis. Here, we review the current evidence for how α-synuclein present in the extracellular milieu may act at the cell surface to drive components of disease progression. A more detailed understanding of the important extracellular interactions of α-synuclein with neuronal and non-neuronal cell types both in the brain and periphery may provide new therapeutic targets to modulate the disease process.

Keywords: chaperone; gliosis; glymphatic; multiple system atrophy; neuroinflammation; α-synuclein.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Interactions of α-synuclein with CNS cell types and the extracellular matrix in multiple system atrophy. α-Syn is released by neurons via either exocytosis or membrane leakage due to apoptosis, necrosis, or other damage. Neurons have LAG3 and TM9SF2 receptors on the surface which when bound by fibrillar α-syn, mediate clathrin-dependent endocytosis. Tunneling nanotubes can mediate α-syn transfer between various cell types. Released α-syn can interact with extracellular proteases and chaperones. Astrocytes detect α-syn and signal for microglial recruitment by inflammatory factors. This also has the effect of activating microglia from the surveillant state to the phagocytic phenotype. Activation is also caused when microglia detect α-syn either in exosomes or free in the extracellular matrix. Astrocytic activation could lead to loss of aquaporin-4 polarization to endfeet and dysregulation of glymphatic circulation. Oligodendrocytes can take up α-syn -containing exosomes from neurons via endocytosis and mediated by surface heparin sulfate proteoglycans (HSPGs). Microglia can engulf exosomes via macropinocytosis. Microglia perform phagocytosis on free and exosome-associated α-syn. Microglia undergo clathrin-mediated endocytosis as well as activation by CD36 scavenger receptor and toll-like receptors (TLRs) and can spread α-syn pathology by migrating away from the site of uptake.
Figure 2
Figure 2
Differential interactions of extracellular α-syn in MSA, PD and DLB. Hypothetical scheme highlighting the differences in pathology that may arise due to variations in abundance, spread and strains of extracellular α-syn. All three diseases have reduced α-syn in CSF samples compared to controls and AD, indicating normal α-syn clearance is decreased or dysfunctional which might be due to altered glymphatic system and astrocytes. Microglial activation and clearance of α-syn by microglia is reduced in PD compared to MSA. Increased oligodendrocyte and astrocyte accumulation of α-syn by uptake in MSA suggests increased brain extracellular α-syn. Neurons show some α-syn pathology in MSA but this tends to be intranuclear and in areas related to neurodegeneration but also varies in cellular localization throughout the brain. Myelinating oligodendrocytes form GCIs whereas oligodendrocyte precursor cells do not. Whereas, non-myelinating oligodendrocytes develop α-syn pathology in PD but not until late stages. Oligodendrocytes may transmit α-syn between themselves along myelinating tracts. Protoplasmic astrocytes develop non-phosphorylated α-syn pathology in PD and are associated with a non-reactive, degenerative phenotype. Astrocytes are highly activated in MSA but α-syn accumulation is more correlated with age-related astrocyte gliopathy. α-Syn ribbons are taken up by oligodendrocytes and fibrils by neurons.

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