Single protein may hold secret to treating Parkinson's disease and more

December 26, 2016, Gladstone Institutes
Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson's disease. Credit: Wikipedia

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 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 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 . 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 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 α-synuclein from the . For mutant LRRK2, Nrf2 drove the protein to gather into incidental clumps that can remain in the cell without damaging it. For α-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 ," 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 regulation pathway that interact with Nrf2 to improve cell health and that may be easier to drug.

Explore further: Unique protein interaction may drive most common genetic cause of Parkinson's disease

More information: Nrf2 mitigates LRRK2- and α-synuclein–induced neurodegeneration by modulating proteostasis, PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1522872114

Related Stories

Unique protein interaction may drive most common genetic cause of Parkinson's disease

January 7, 2014
The most devastating aspect of Parkinson's disease may not be its debilitating symptoms, which rob its victims of their ability to control their own movement. It may not be the millions around the world and their families ...

Discovery may lead to a treatment to slow Parkinson's disease

July 19, 2016
Using a robust model for Parkinson's disease, University of Alabama at Birmingham researchers and colleagues have discovered an interaction in neurons that contributes to Parkinson's disease, and they have shown that drugs ...

Failure to destroy toxic protein—not buildup of protein itself—contributes to Huntington's disease

July 21, 2013
Alzheimer's, Huntington's, Parkinson's. Names forever linked to what they represent: diseases that ravage the brain's neurons and leave entire regions to wither and die. These and other so-called neurodegenerative diseases ...

Prevention of sickle cell disease progression in adult mice

April 7, 2016
Sickle cell disease (SCD) is characterized by abnormal hemoglobin, which alters the shape of red blood cells, resulting in poor blood flow and eventual death. In developed countries, the survival rate in children with SCD ...

Novel compound has promise for treatment of Huntington's disease

July 14, 2016
A major, multi-institutional study based at Massachusetts General Hospital (MGH) has identified a promising treatment strategy for Huntington's disease (HD). In their report receiving online publication in Cell Chemical Biology, ...

Recommended for you

Key factor in development of Parkinson's disease identified

April 20, 2018
A molecule has been identified that appears to play an important role in the development of Parkinson's disease, a debilitating disease that affects millions of people around the world.

Augmented reality app may aid patients with Parkinson's

April 12, 2018
It's appropriate that during Parkinson's Awareness Month, a team of Rice University seniors will show how augmented reality may help patients with the disease.

Are people with Parkinson's disease depressed or demoralized?

April 4, 2018
People with Parkinson's disease who show signs of depression may actually have a condition called demoralization, according to a study published in the April 4, 2018, online issue of Neurology, the medical journal of the ...

Mobile apps could hold key to Parkinson's research, care

March 27, 2018
A new study out today in the journal JAMA Neurology shows that smartphone software and technology can accurately track the severity of the symptoms of Parkinson's disease. The findings could provide researchers and clinicians ...

Parkinson's gene initiates disease outside of the brain

March 21, 2018
Until very recently, Parkinson's had been thought a disease that starts in the brain, destroying motion centers and resulting in the tremors and loss of movement. New research published this week in the journal Brain, shows ...

Faulty cellular membrane 'mix' linked to Parkinson's disease

March 15, 2018
Working with lab-grown human brain cells, Johns Hopkins researchers report they have uncovered a much sought-after connection between one of the most common genetic mutations in Parkinson's disease and the formation of fatty ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.