Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein

Abstract

Manganese exposure promotes α-synuclein propagation, neuroinflammation, and neurodegeneration. Manganese in Parkinson’s disease Manganese is an essential mineral, but chronic exposure to high amounts of it, such as is experienced by welders, is associated with symptoms of Parkinson’s disease. A hallmark of the disease is aggregation of the protein α-synuclein (αSyn), which is toxic to neurons. Harischandra et al. found that extracellular vesicles called exosomes isolated from serum collected from welders contained misfolded αSyn. In cell culture and mouse models, exposure to manganese or to isolated, manganese-induced exosomes promoted the transfer of αSyn between neurons and microglia, which induced inflammation and neuronal cell death. These findings further explain the role of manganese in neurodegenerative disease. The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn2+) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson’s disease. In cultured dopaminergic neuronal cells stably expressing wild-type human αSyn, misfolded αSyn was secreted through exosomes into the extracellular medium upon Mn2+ exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn2+-elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn2+ accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn2+ exposure. Welders exposed to Mn2+ had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn2+-treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn2+ exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.