Editors' ChoiceNeurodegeneration

Linking Mn2+, α-synuclein, and neuroinflammation

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Sci. Signal.  12 Mar 2019:
Vol. 12, Issue 572, eaax1045
DOI: 10.1126/scisignal.aax1045

Several studies elucidate the molecular links between manganese exposure and Parkinson’s disease.

Parkinson’s disease (PD) is a neurodegenerative disease that impairs motor function and control, as well as cognition and more general neurological functions in patients with advanced disease. The incidence of PD is particularly high among welders, who are chronically exposed to fumes that contain manganese (Mn2+). In this issue of Science Signaling, Harischandra et al. identified how Mn2+ contributes directly to PD pathology. A hallmark of PD is the aggregation and spread of a misfolded version of the protein α-synuclein, which is toxic to neurons. The authors found that extracellular vesicles called exosomes isolated from the serum of welders contained misfolded α-synuclein. In cell culture and mouse models, exposure to manganese or to isolated Mn2+-induced exosomes promoted the transfer of α-synuclein between neurons and microglia, which induced inflammation and neuronal cell death. In another study in the Science Signaling Archives, the Kanthasamy laboratory (see Sarkar et al.) also discovered that plasma exosomes from welders contained the inflammasome components NLRP3 and ASC, which were also in exosomes released from Mn2+-exposed microglial cells. The authors connected the inflammasome activation and release to Mn2+-induced mitochondrial stress. Curiously, Gordon et al. (in a study coauthored by Kanthasamy) showed that fibrillar α-synuclein induced microglial release of ASC, which subsequently promoted α-synuclein aggregation and dopaminergic neuronal death. These studies reveal how Mn2+ contributes to PD-associated propagation of both α-synuclein and neuroinflammation through linked mechanisms involving intercellular communication between neurons and microglia. These findings may lead to new therapies for patients.

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