A recent study offers new information regarding an important cellular protein (Nrf2) which could facilitate the treatment of neurodegenerative diseases like Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS) and Huntington’s disease.
As to their origin, these diseases are caused by proteins which misbehave in the brain. The proteins misfold and build up in neurons, causing damage and finally destroying the cells. In the study, researchers at the Gladstone Institutes used another protein, Nrf2, to reinstate the disease-causing proteins levels within the healthy range, thus avoiding cell death.
The researchers used two models of Parkinson’s disease to test Nrf2. One model had cells with mutations in the LRRK2 protein and the other model had cells with mutant alpha-synuclein protein. By triggering Nrf2, the researchers enabled various “house-cleaning” processes in the cell to eliminate excess LRRK2 and alpha-synuclein.
How Nrf2 works?
“Nrf2 organizes a whole series of gene expression, however we didn’t know how significant it was for managing protein levels till now,” described first author Gaia Skibinski, PhD, who serves as a staff research scientist at Gladstone. “Nrf2 overexpression in cellular models of Parkinson’s disease showed a massive effect. Actually, it saves cells from the disease in a better way than all others we’ve found.”
The scientists made use of both neurons of rat neurons and human neurons developed from stimulated pluripotent stem cells. Then neurons were programmed for Nrf2 expression along with mutant LRRK2 oralpha-synuclein. With the help of a unique robotic microscope crafted by the Finkbeiner laboratory, the researchers labeled and observed individual neurons eventually to examine their overall health and protein levels. They took multiple images of the cells for more than a week, determining the progress and death of each one.
The scientists found that Nrf2 functioned in various ways to facilitate elimination of mutant alpha-synuclein or LRRK2 from the cells. For mutant LRRK2, Nrf2 made the protein assemble into incidental clumps that can stay in the cell without destroying it. For alpha-synuclein, Nrf2 intensified the clearance and breakdown of the protein, decreasing its levels in the cell.
“I am highly interested about this approach for neurodegenerative diseases treatment,” mentioned Finkbeiner, a senior investigator at Gladstone and senior author on the study. “We’ve examined Nrf2 in models of Parkinson’s disease, Huntington’s disease and ALS, and it is the major protective thing we’ve ever known. As per the level and the extent of the effect, we in fact want to study Nrf2 and its function in protein regulation as well.”
The scientists note that Nrf2 itself can be hard to target with a drug since it is associated with so many cellular processes, so they are currently concentrating on a few of its downstream effects. They anticipate to find other players in the regulating protein pathway that communicate with Nrf2 to enhance cell health and that can be simpler to treat.