Abstract
Recent researches regarding to exosomal involvement in alpha-synuclein (α-syn) transmission relating to the pathological process of Parkinson’s disease (PD) have attracted considerable attention. It is highly desirable to make clear the diffusion process and cellular uptake of α-syn-associated exosomes and the underlying mechanism of exosomes-involved communication in the synucleinopathy pathogenesis. To determine the contribution of α-syn-associated exosomes to the initiation and progression of PD, plasma exosomes derived from PD patients were stereotaxically injected into the striatum of mice brains. Exosomes extracted from plasma diagnosed with PD contained monomeric and oligomeric α-syn. Here, we found that microglia display a high potency for uptake of plasma exosomes derived from PD patients, and therefore could be activated by exogenous exosomes in vitro and in vivo. In addition, immunofluorescent double staining verified the transfer of exogenous human exosomal α-syn to neurons. The release of human exosomal α-syn from microglia may facilitate this propagation. Finally, we described a mechanism underlying this potential role of microglia in the transmission of exosomal α-syn. Specifically, exogenous exosomes were found to dysregulate autophagy of the BV2 mouse microglia cell line with presentation of increased accumulation of intracellular α-syn and accelerated secretion of α-syn into extracellular space. These results suggest that microglia play a crucial role in the transmission of α-syn via exosomal pathways, in additional to idea that the progression of PD may be altered by the modulation of exosome secretion and/or microglial states.
Highlights
Parkinson’s disease (PD) is a neurodegenerative movement disorder that is neuropathologically characterized by the accumulation of intraneuronal alpha-synuclein (α-syn)[1,2]
The concentrations of total α-syn in plasma-derived exosomes were determined by Enzyme-linked immunosorbent assay (ELISA) and were found to be significantly higher in PD exosomes compared to the controls (Fig. 2a)
The positive signal obtained using antibody α-syn in super-resolution imaging, suggested that α-syn is partly exposed on the surface of plasma exosomes derived from PD patients (PD-EXO) (Fig. 2b)
Summary
Parkinson’s disease (PD) is a neurodegenerative movement disorder that is neuropathologically characterized by the accumulation of intraneuronal alpha-synuclein (α-syn)[1,2]. A growing body of evidence from animal models, as well as data from cultured cells and human postmortem brains, support the idea that α-syn can propagate from cell to cell, suggesting an important role of extracellular α-syn in its aggregation[3,4,5,6]. Some recent studies demonstrated that α-syn aggregates could be induced by the introduction of exosomal α-syn derived from patients with synucleinopathies into cultured cells or wild-type mice[15,19]. A subset of extracellular vesicles, have recently been detected to penetrate the blood–brain barrier and may result in the spread of brain protein to the plasma pool[20,21,22]. The intracellular accumulation of α-syn has been associated with the dysfunction of mitochondrial metabolism, ubiquitinproteasome system, autophagy–lysosomal pathway, endoplasmic reticulum stress, and calcium homeostasis[26]
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