A new way to regulate protein levels and functions could be the answer to treating devastating neurological conditions
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, MD, PhD, 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 a-synuclein. By activating Nrf2, the researchers turned on several “house-cleaning” mechanisms in the cell to remove excess LRRK2 and a-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, PhD, 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 Proceedings of the National Academy of Sciences, 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 a-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.
The scientists discovered that Nrf2 worked in different ways to help remove either mutant LRRK2 or a-synuclein from the cells. For mutant LRRK2, Nrf2 drove the protein to gather into incidental clumps that can remain in the cell without damaging it. For a-synuclein, Nrf2 accelerated the breakdown and clearance of the protein, reducing its levels in the cell.
“I am very enthusiastic about this strategy for treating neurodegenerative diseases,” said Finkbeiner, a senior investigator at Gladstone and senior author on the paper. “We’ve tested Nrf2 in models of Huntington’s disease, Parkinson’s disease, and ALS, and it is the most protective thing we’ve ever found. Based on the magnitude and the breadth of the effect, we really want to understand Nrf2 and its role in protein regulation better.”
The scientists say that Nrf2 itself may be difficult to target with a drug because it is involved in so many cellular processes, so they are now focusing on some of its downstream effects. They hope to identify other players in the protein regulation pathway that interact with Nrf2 to improve cell health and that may be easier to drug.
Receive an email update when we add a new NEURODEGENERATIVE DISEASES article.
The Latest on: Regulate protein levels and functions
via Google News
The Latest on: Regulate protein levels and functions
- Scientists uncover functions of mysterious organelles and their relation to stresson December 1, 2019 at 1:48 am
This is important because intron retention regulates gene expression for a variety of biological functions ... which are molecules copied from DNA, but not translated into proteins. Hirose and his ...
- Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescenceon November 28, 2019 at 3:13 pm
The levels of the senescence molecular ... 26 These expanded functions make AARSs a good bridge between protein homeostasis (proteostasis) and other cellular and biological processes, such as cellular ...
- Jennie: MCG Researchers identify link between high glucose and function of circadian clocks in cellson November 26, 2019 at 8:30 am
You know, those cells that help regulate the timing of our bodies functions ... some of which our body also breaks down into glucose, dampens clock function and imperils cardiovascular health. “It’s ...
- The deubiquitinase USP10 regulates KLF4 stability and suppresses lung tumorigenesison November 20, 2019 at 5:23 am
the deubiquitinases of KLF4 and the regulatory function remain unexplored. Here, by screening ubiquitin-specific proteases that may interact with KLF4, we found ubiquitin-specific peptidase 10 (USP10) ...
- New approach uses light to stabilize proteins for studyon November 4, 2019 at 9:14 am
Using light, a method called optogenetics, is a more efficient, nontoxic way to control protein levels, Zhang said ... new optogenetic technique that will help scientists study protein function.
- III: Medium: Collaborative Research: Multi-level computational approaches to protein function predictionon October 12, 2019 at 2:22 pm
Proteins are ... new drug treatments to regulate the processes for improving human health. The task is however highly non-trivial in modern molecular biology studies. The most accurate method to ...
- How a protein connecting calcium and plant hormone regulates plant growthon September 26, 2019 at 10:00 am
Yalovsky. "Now we know that when auxin levels are high, the levels of the newly discovered binding protein CMI1 are high. We discovered that this protein regulates auxin responses and calcium levels ...
- Dopamine and serotonin: Brain chemicals explainedon August 19, 2019 at 10:06 am
Dopamine levels also influence the ... gene affect how the dopamine transporter proteins function. Dopamine transporter deficiency syndrome disrupts dopamine signaling, which impacts the body's ...
- Study identifies proteins that interact with processes regulating gene p53on June 23, 2019 at 11:05 pm
We found one of the proteins discovered in this screen called DBC1 is critical to maintaining the levels ... regulates CBP activity, and therefore plays an essential role in maintaining p53 activity ...
via Bing News