One single protein could be the key to developing groundbreaking treatments for various neurodegenerative diseases including Alzheimer’s, Huntington’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS). What these diseases all have in common are that they’re triggered by proteins misfolding and accumulating in neurons within the brain. This causes devastating damage to the cells, eventually killing them off. However, in a new study carried out by Steven Finkbeiner MD, Ph.D., and the team at the Gladstone Institutes they discovered a protein called Nrf2 was able to prevent cell death by restoring the disease-causing proteins back up to a healthy range.
The Nrf2 protein was tested in two different Parkinson’s disease models which consisted of cells with mutated versions of the protein LRRK2 and a–synuclein. With the Nrf2 activated, the cell was able to remove excess LRRK2 and a-synuclein from it. Gaia Skibinski, Ph.D., and a staff research scientist at Gladstone say. “Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now. 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.”
During the study, the researchers used both rat and human neurons created from induced pluripotent stem cells and programmed then to express Nrf2 plus either a-synuclein or LRRK2. The researchers then marked and tracked the individual neurons over a period to analyze their protein levels and to keep an eye on their overall health too. During the study, the researchers discovered that the way in which Nrf2 worked to remove either LRRK2 or a-synuclein from the cells differed depending on which it was. For removing LRRK2, NRrf2 forced the protein to form into clumps that stayed within the cells without causing it any harm. With regards to the a-synuclein, Nrf2 reduced the levels of the protein within the cell by accelerating the breakdown and clearance of it.
Finkbeiner is senior author on the paper, and he says, “I am very enthusiastic about this strategy for treating neurodegenerative diseases. We’ve tested Nrf2 in models of Huntington’s disease, Parkinson’s disease, and ALS, and it is the most protective thing we’ve every found. Based on the magnitude and the breadth of the effect, we want to understand Nrf2 and its role in protein regulation better.” The team is now hoping to discover other key players in the protein regulation process that can interact with Nrf2 to produce more positive results.