New details learned about a key cellular protein could lead to treatments for neurodegenerative diseases, such as Parkinson's, Huntington's, Alzheimer's, and amyotrophic lateral sclerosis (ALS). At their root, these disorders are triggered by misbehaving proteins in the brain. The proteins misfold and accumulate in neurons, inflicting damage and eventually killing the cells. In a new study, researchers in the laboratory of Steven Finkbeiner, M.D., Ph.D., at the Gladstone Institutes used a different protein, Nrf2, to restore levels of the disease-causing proteins to a normal, healthy range, thereby preventing cell death. The researchers tested Nrf2 in two models of Parkinson's disease: cells with mutations in the proteins LRRK2 and α-synuclein. By activating Nrf2, the researchers turned on several "house-cleaning" mechanisms in the cell to remove excess LRRK2 and α-synuclein. "Nrf2 coordinates a whole program of gene expression, but we didn't know how important it was for regulating protein levels until now," explained first author Gaia Skibinski, Ph.D., a staff research scientist at Gladstone. "Overexpressing Nrf2 in cellular models of Parkinson's disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we've found." In the study, published in the early online edition of PNAS, the scientists used both rat neurons and human neurons created from induced pluripotent stem cells. They then programmed the neurons to express Nrf2 and either mutant LRRK2 or α-synuclein. Using a one-of-a-kind robotic microscope developed by the Finkbeiner laboratory, the researchers tagged and tracked individual neurons over time to monitor their protein levels and overall health. They took thousands of images of the cells over the course of a week, measuring the development and demise of each one.
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