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

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

Publication date: Mar 12, 2019

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 (Mn) 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 Mn exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn-elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn exposure. Welders exposed to Mn had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn-treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.

Concepts Keywords
Caveolae Manganese
Complementation Synucleinopathy
Divalent Prion
Dopaminergic Neurodegeneration
Endocytosed Exosome
Exosomes Amyloidosis
Extracellular Medium Genetics
Fluorescence Vesicles
Manganese Neurological disorders
Mice Branches of biology
Microglial Cells Disease
Misfolding Metal
Neurodegenerative
Neurodegenerative Disorders
Neurotoxic
Neurotoxicity
Parkinson
Parkinsonian
Pathology
Pathophysiological
Prion
Sci
Serum
Stress
Striatum
Vesicles
Wild Type

Semantics

Type Source Name
disease DOID neurotoxicity
disease DOID synucleinopathies
disease MESH neurodegenerative disorders
gene UNIPROT SYNM
gene UNIPROT FYN
drug DRUGBANK Manganese

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