Corporate Banner
Satellite Banner
Stem Cells, Cellular Therapy & Biobanking
>
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Too Much Protein May Kill Brain Cells As Parkinson’s Progresses

Published: Friday, April 11, 2014
Last Updated: Friday, April 11, 2014
Bookmark and Share
NIH-funded study on key Parkinson’s gene finds a possible new target for monitoring the disease.

Scientists may have discovered how the most common genetic cause of Parkinson’s disease destroys brain cells and devastates many patients worldwide.  The study was partially funded by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS); the results may help scientists develop new therapies.

“This may be a major discovery for Parkinson’s disease patients,” said Ted Dawson, M.D., Ph.D., director of the Johns Hopkins University (JHU) Morris K. Udall Center of Excellence for Parkinson’s Disease, Baltimore, MD.  Dr. Dawson and his wife Valina Dawson, Ph.D., director of the JHU Stem Cell and Neurodegeneration Programs at the Institute for Cell Engineering, led the study published in Cell.

The investigators found that mutations in a gene called leucine-rich repeat kinase 2 (LRRK2; pronounced “lark two” or “lurk two”) may increase the rate at which LRRK2 tags ribosomal proteins, which are key components of protein-making machinery inside cells. This could cause the machinery to manufacture too many proteins, leading to cell death.

“For nearly a decade, scientists have been trying to figure out how mutations in LRRK2 cause Parkinson’s disease,” said Margaret Sutherland, Ph.D., a program director at NINDS. “This study represents a clear link between LRRK2 and a pathogenic mechanism linked to Parkinson’s disease.” 

Affecting more than half a million people in the United States, Parkinson’s disease is a degenerative disorder that attacks nerve cells in many parts of the nervous system, most notably in a brain region called the substantia nigra, which releases dopamine, a chemical messenger important for movement. Initially, Parkinson’s disease causes uncontrolled movements; including trembling of the hands, arms, or legs. As the disease gradually worsens, patients lose ability to walk, talk or complete simple tasks.

For the majority of cases of Parkinson’s disease, a cause remains unknown. Mutations in the LRRK2 gene are a leading genetic cause. They have been implicated in as many as 10 percent of inherited forms of the disease and in about 4 percent of patients who have no family history. One study showed that the most common LRRK2 mutation, called G2019S, may be the cause of 30-40 percent of all Parkinson’s cases in people of North African Arabic descent.

LRRK2 is a kinase enzyme, a type of protein found in cells that tags molecules with chemicals called phosphate groups. The process of phosphorylation helps regulate basic nerve cell function and health. Previous studies suggest that disease-causing mutations, like the G2019S mutation, increase the rate at which LRRK2 tags molecules. Identifying the molecules that LRRK2 tags provides clues as to how nerve cells may die during Parkinson’s disease.

In this study, the researchers used LRRK2 as bait to fish out the proteins that it normally tags.  Multiple experiments performed on human kidney cells suggested that LRRK2 tags ribosomal proteins. These proteins combine with other molecules, called ribonucleic acids, to form ribosomes, which are the cell’s protein-making factories.  

Further experiments suggested that disease-causing mutations in LRRK2 increase the rate at which it tags two ribosomal proteins, called s11 and s15. Moreover, brain tissue samples from patients with LRRK2 mutations had greater levels of phosphorylated s15 than seen in controls.

Next, the researchers investigated whether phosphorylation could be linked to cell death, by studying nerve cells derived from rats or from human embryonic stem cells. Genetically engineering the cells to have a LRRK2 mutant gene increased the amount of cell death and phosphorylated s15.  In contrast, the researchers prevented cell death when they engineered the cells to also make a mutant s15 protein that could not be tagged by LRRK2.  

“These results suggest that s15 ribosome protein may play a critical role in the development of Parkinson’s disease,” said Dr. Dawson. 

How might phosphorylation of s15 kill nerve cells? To investigate this, Dr. Dawson and his colleagues performed experiments on fruit flies.  

Previous studies on flies showed that genetically engineering dopamine-releasing nerve cells to overproduce the LRRK2 mutant protein induced nerve cell damage and movement disorders. Dr. Dawson’s team found that the brains of these flies had increased levels of phosphorylated s15 and that engineering the flies so that s15 could not be tagged by LRRK2 prevented cell damage and restored normal movement.  

Interestingly, the brains of the LRRK2 mutant flies also had abnormally high levels of all proteins, suggesting that increased s15 tagging caused ribosomes to make too much protein. Treating the flies with low doses of anisomycin, a drug that blocks protein production, prevented nerve cell damage and restored the flies’ movement even though levels of s15 phosphorylation remained high.

“Our results support the idea that changes in the way cells make proteins might be a common cause of Parkinson’s disease and possibly other neurodegenerative disorders,” said Dr. Dawson.

Dr. Dawson and his colleagues think that blocking the phosphorylation of s15 ribosomal proteins could lead to future therapies as might other strategies which decrease bulk protein synthesis or increase the cells’ ability to cope with increased protein metabolism. They also think that a means to measure s15 phosphorylation could also act as a biomarker of LRRK2 activity in treatment trials of LRRK2 inhibitors. 

This work was supported by grants from the NINDS (NS038377, NS072187), the JPB Foundation, the Maryland Stem Cell Research Fund (2007-MSCRFI-0420-00, 2009-MSCRFII-0125-00, 2013-MSCRFII-0105-00), and the New York Stem Cell Foundation. 


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 4,000+ scientific posters on ePosters
  • More than 5,300+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Gene Editing Corrects Sickle Cell Mutation
Researchers demonstrate a potential pathway to developing gene-editing treatments for sickle cell disease.
Wednesday, October 26, 2016
$12.4M Awarded to Neural Regeneration Projects
The National Institutes of Health will fund six projects to identify biological factors that influence neural regeneration.
Friday, September 02, 2016
Stem Cell Therapy Heals Injured Mouse Brain
A team of researchers has developed a therapeutic technique that dramatically increases the production of nerve cells in mice with stroke-induced brain damage.
Tuesday, August 23, 2016
Stem Cells Grown On Scaffold Mimic Hip Joint Cartilage
Adult fat-derived stem cells grown on a 3-D scaffold that mimicked a hip joint surface formed cartilage and maintained the correct shape.
Wednesday, August 10, 2016
Using Animal Embryos Containing Human Cells
With recent advances in stem cell and gene editing technologies, an increasing number of researchers are interested in growing human tissues and organs in animals by introducing pluripotent human cells into early animal embryos.
Monday, August 08, 2016
Treatment Advancement for Gaucher and Parkinson's Diseases
NIH scientists identify molecule that may act as a possible treatment of neurological diseases.
Wednesday, July 13, 2016
NIH Funds Million-Person Medicine Study
NIH announces $55million in awards to build foundations for ambitious Cohort Program that aims to engage 1 million participants in lifestyle, environments and genetics research.
Friday, July 08, 2016
Manufactured Stem Cells To Advance Clinical Research
Clinical-grade cell line will enable development of new therapies and accelerate early-stage clinical research.
Tuesday, June 28, 2016
NIH Funds Biobank To Support Precision Medicine Initiative Cohort Program
$142 million over five years will be awarded to the Mayo Clinic to establish the world’s largest research-cohort biobank for the PMI Cohort Program
Friday, May 27, 2016
Molecule Proves Key to Brain Repair After Stroke
Scientists found that a molecule known as growth and differentiation factor 10 (GDF10) plays a key role in repair mechanisms following stroke.
Tuesday, November 10, 2015
A Patient’s Budding Cortex — In A Dish?
Networking neurons thrive in 3-D human “organoid”
Friday, May 29, 2015
Drugs that Activate Brain Stem Cells May Reverse Multiple Sclerosis
NIH-funded study identifies over-the-counter compounds that may replace damaged cells.
Tuesday, April 21, 2015
Stem Cell Transplants May Halt Progression of Multiple Sclerosis
NIH-funded study yields encouraging early results.
Tuesday, December 30, 2014
Scientists Sniff Out Unexpected Role for Stem Cells in the Brain
NIH scientists find that restocking new cells in the brain’s center for smell maintains crucial circuitry.
Saturday, October 11, 2014
Suspect Gene Corrupts Neural Connections
“Diseases of synapses” demo’d in a dish - NIH-funded study.
Tuesday, August 19, 2014
Scientific News
Stem Cells in Drug Discovery
Potential Source of Unlimited Human Test Cells, but Roadblocks Remain.
Improving Drug Production with Computer Model
A model has been developed that can be used to improve and accelerate the production of biotherapeutics, cancer drugs, and vaccines.
Defining Immortality of Stem Cells
Researchers defined the mechanisms underlying increased protein quality control of pluripotent stem cells.
BioCision Forms MedCision
The new company will focus on technologies for the management and automation of vital clinical processes.
Enhancing CRISPR to Explore Further
Researchers have developed sOPTiKO, a more efficient and controllable CRISPR genome editing platform.
Regenerating Diseased Hearts
Researchers from the University of Otago have probed the potential of adult stem cell types to repair diseased hearts.
Stem Cells Police Themselves to Reduce Scarring
Scientists have discovered stem cells in muscle fibers change gene expressions to respond to injury.
Bright Red Fluorescent Protein Created
Scientists have created a bright red, fluorescent protein that could be used to track essential cellular processes.
Protein Self-Regulates Abundance
Researchers have uncovered how a protein, that plays a crucial role in embryonic stem cell renewal, is regulated.
Topical Immunotherapy Effective Against Early Skin Cancer
Combination of two commonly used drugs triggers immune response against precancerous skin lesions.
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
4,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,300+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!