Novel Exosome-Based Biomarker Discovery for Metal Mixture Exposure, Relevance to Parkinson s Disease
Abstract
Available evidence suggests that overexposure to metals, such as manganese, has neurotoxic effects in humans. Long-term or chronic exposure to neurotoxic doses of certain metals can trigger a cell-signaling cascade favoring persistent, heightened levels of oxidative stress, protein misfolding, and neuroinflammatory processes. Manganese and vanadium (Mn/V) are preferred metals in the rising production of special steels and temperature-resistant alloys as they are among some of the lightest metals with an inherent high strength. Mn induces a Parkinsonian syndrome known as manganism. Mn also can interact with V to enhance the onset of chronic neurological conditions. Importantly, our preliminary studies show that co-exposure to Mn/V induces more pronounced neurotoxic responses compared to individual metal exposures. Therefore, inhalation of fumes and dust containing mixed metals such as Mn/V produced during industrial manufacturing poses potential health concerns for workers at both civilian and DoD-related installations. Exosomes are nano-scale, cell-derived vesicles containing biomolecular cargo that get released into the extracellular space. Biomedical research on exosomes has been growing in recent years because of their potential role in disease pathogenesis and biomarker discovery, with a strong focus on Parkinson s disease (PD). Exosomes can directly stimulate neighboring cells by receptor-mediated interactions or may transfer from the cell of origin to various bioactive molecules including membrane receptors, proteins, mRNAs, and microRNAs. Importantly, our lab and others have shown that exosomes carry pathologic, misfolded protein cargo that can propagate deleterious effects from cell-to-cell in neurodegenerative disorders. Recently, we obtained very exciting results in a newly developed, ultrasensitive protein-misfolding assay that can detect the PD-relevant protein alpha-synuclein in the serum exosomes of Mn fume-exposed welders. Thus, the overarching hypothesis of our proposal is that Mn/V co-exposure exacerbates metal neurotoxicity in the brain and enhances the measurable biomarkers relevant to the metal-induced neurodegeneration underlying PD. We will evaluate and validate exosome-based biomarkers including misfolded alpha-synuclein aggregates, miRNAs, and lipids in animal models of Mn/V neurotoxicity and in human serum isolated from welders occupationally exposed to Mn/V. Successful completion of the proposed studies will establish novel, clinically relevant biomarkers for monitoring Mn/V exposure levels that could pose an occupational risk of PD throughout the complex of civilian and military industrial facilities.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810106
Entities
People
- Anumantha G Kanthasamy
Organizations
- Iowa State University
- United States Army