Researchers Uncover Coppers Role in Prion Protein Misfolding
Anumantha Kanthasamy, Ph.D., Sanjeevi Sivasankar, Ph.D.
Iowa State University
R01ES019267 and ViCTER supplement
NIEHS grantees have described how copper ions cause prion proteins to misfold, which then seeds the misfolding and clumping of nearby prion proteins. The work also established a molecular-level link between copper exposure and prion protein neurotoxicity, providing insight into the role of metals in prion, Alzheimer's, and Parkinson's diseases, which all involve protein misfolding.
Prions are abnormal, pathogenic agents that are transmissible and can induce abnormal folding of specific normal cellular proteins called prion proteins that are found most abundantly in the brain. The abnormal folding of prion proteins leads to brain damage and symptoms of neurodegenerative disease.
The researchers studied the prion proteins using integrated biophysical and neurotoxicological research approaches. They developed a fluorescence-based technique that identified misfolded prion proteins with single-molecule sensitivity and used it to show that misfolding begins when copper ions bind to the unstructured tail of the prion protein. Using single-molecule force spectroscopy to measure the efficiency of prion protein clumping, they found that misfolded prion proteins stick together nearly 900 times more efficiently than normally folded proteins. They also studied brain tissue from mice, finding that the copper-induced misfolding and clumping is associated with inflammation and damage to nerve cells in brain tissue. Overall, the findings identify the biophysical conditions and mechanisms for copper-induced prion protein misfolding, clumping, and neurotoxicity.
Citation: Citation: Yen CF, Harischandra DS, Kanthasamy A, Sivasankar S. 2016. Copper-induced structural conversion templates prion protein oligomerization and neurotoxicity. Sci Adv. 2(7):e1600014.
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