Anumantha Kanthasamy, Ph.D.
Iowa State University
R01ES026892, R01ES019267, R01ES025991
NIEHS grantees discovered how manganese exposure can lead to aggregation and spread of a misfolded version of the alpha-synuclein protein, which is toxic to nerve cells and a hallmark of Parkinson’s disease. The study provides new information about the biological processes that link manganese exposure and the onset of Parkinson’s-like symptoms.
In a study using cells found within the nervous system, the researchers found that manganese induced alpha-synuclein misfolding and stimulated the packaging of these misfolded proteins into exosomes, which are small membrane-bound structures secreted by cells. This process provides a way for the misfolded proteins to transfer from cell to cell to propagate. They found that the exosomes containing alpha-synuclein mounted an inflammatory response and led to neurotoxic effects.
Looking at the same process in mice, they found that manganese accelerated the cell-to-cell transmission of misfolded alpha-synuclein, which resulted in neurodegenerative effects. They also analyzed blood serum samples from welders and found that welders exposed to manganese had increased misfolded alpha-synuclein content in their serum exosomes.
Although previous studies have shown links between alpha-synuclein misfolding and manganese, this study provides new evidence for how manganese facilitates progression of neurological disease. According to the authors, the analysis of serum exosomes may also provide a new way to detect the presence of misfolded alpha-synuclein proteins, which could lead to earlier detection of Parkinson’s disease.
Citation: Harischandra DS, Rokad D, Neal ML, Ghaisas S, Manne S, Sarkar S, Panicker N, Zenitsky G, Jin H, Lewis M, Huang X, Anantharam V, Kanthasamy A, Kanthasamy AG. 2019. Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of alpha-synuclein. Sci Signal 12(572).