Corporate Banner
Satellite Banner
Proteomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Failure to Destroy Toxic Protein Contributes to Progression of Huntington’s Disease

Published: Tuesday, July 23, 2013
Last Updated: Tuesday, July 23, 2013
Bookmark and Share
Gladstone-led study also finds target that boosts protein clearance, prolongs cell life.

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 are often associated with the buildup of toxic proteins that lead to neuronal death.

But now, scientists at the Gladstone Institutes have discovered that the progression of disease is not due to the buildup of toxins itself, but rather in the individual neurons’ ability to dissolve them. Further, they have identified a therapeutic target that could boost this ability, thereby protecting the brain from the diseases’ deadly effects.

In the latest issue of Nature Chemical Biology, researchers in the laboratory of Gladstone investigator Steve Finkbeiner, MD, PhD, describe how a newly developed technology allowed them to see – for the first time – how individual neurons fight back against the buildup of toxic proteins over time. Focusing their efforts on a model of Huntington’s disease, the team observed how different types of neurons in the brain each responded to this toxic buildup with different degrees of success, offering clues as to why the disease causes neurons in one region to die, while neurons in another are spared.

“Huntington’s – an inherited and fatal disorder that leads to problems with muscle coordination, cognition and personality – is characterized by the toxic buildup of a mutant form of the huntingtin protein in the brain,” explained Finkbeiner, who directs the Taube-Koret Center for Neurodegenerative Disease Research at Gladstone. Finkbeiner is also a professor of neurology and physiology at UC San Francisco, with which Gladstone is affiliated.

“A long-standing mystery among researchers was how the buildup of this mutant huntingtin caused cells to degrade and die, but previous technology made it virtually impossible to monitor this process at the cellular level," he added. "In this study, we employed a method called optical pulse-labeling, or OPL, which allowed us to see how the mutant huntingtin ravaged the brain over time – neuron by neuron.”

Using neurons extracted from rodent models of Huntington’s, the team employed the OPL method, which tracked the speed and efficiency with which different types of neurons were able to break down and dissolve the mutant huntingtin. The faster a cell cleared out the toxins, the longer the neuron survived.

Surprisingly, the research team noticed clear differences in the ability of different types of neurons to clear mutant huntingtin. Neurons located in the striatum – the region of the brain involved in movement that is primarily affected by Huntington’s – were particularly susceptible. However, neurons found in other regions, such as the cortex and cerebellum, were less so. And when they tracked the striatal neurons carrying the mutant huntingtin over time, they found them much more likely to die than those from other brain regions.

All cells depend on two main processes to clear excess proteins: the ubiquitin-proteasome system (UPS) and autophagy. Although their mechanisms are distinct, their goal is the same: to literally gobble up excess proteins, ensuring they are efficiently degraded so as to not to interfere with normal cellular activity.

The research team found that striatal neurons were particularly sensitive to disruptions to the autophagy process. But the team found a way around this problem. They artificially accelerated autophagy by boosting the activity of a protein called Nrf2 in these neurons, which in turn prolonged cell survival.

“If we could develop drugs that boost Nrf2 production in the neurons most susceptible to Huntington’s, we might extend their survival, thereby staving off the worst effects of the disease,” said former Gladstone postdoctoral fellow Andrey Tsvetkov, PhD, the study’s lead author. “Importantly, our results also demonstrate that the brain itself has evolved powerful coping mechanisms against diseases such as Huntington’s. For example, the fact that people don’t start experiencing symptoms of Huntington’s until the fourth or fifth decade of their lives – even though the mutant huntingtin is present at birth – is further evidence of the brain’s ability to stave off the effects of the disease.”

“Our findings are critical not only to inform us as to the underlying mechanisms behind diseases such as Huntington’s, but also to remind researchers that focusing on the disease-causing protein – and not how individual cells respond to it – is only one side of the coin,” added Finkbeiner. “To truly understand a complex disease like Huntington’s, we must also look to the brain’s naturally evolved defense mechanisms, which as we’ve shown here could represent an entirely new therapeutic strategy.”

Montserrat Arrasate, PhD, Sami Barmada, MD, PhD, and Punita Sharma, PhD, also participated in this research at Gladstone, which received support from the National Institute of Neurological Disease and Stroke, the National Institute on Aging, the Huntington’s Disease Society of America, the Taube-Koret Center for Neurodegenerative Disease, the Hereditary Disease Foundation, the Hilblom Foundation, the California Institute for Regenerative Medicine, the National Center for Research Resources and the James E. Bashaw Family.


Further Information
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 2,500+ scientific posters on ePosters
  • More than 3,700+ 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

Industry-Sponsored Academic Inventions Spur Increased Innovation
Analysis questions assumption that corporate support skews science toward inventions that are less useful than those funded by the government or non-profit organizations.
Monday, March 24, 2014
Structure of Key Pain-Related Protein Unveiled
In a technical tour de force, scientists have determined, at near-atomic resolution, the structure of a protein that plays a central role in the perception of pain and heat.
Friday, December 06, 2013
Chemical Signature for Fast Form of Parkinson's Found
The physical decline experienced by Parkinson's disease patients eventually leads to disability and a lower quality of life.
Monday, November 25, 2013
New Insights into How Proteins Regulate Genes
Researchers have developed a new way to parse and understand how special proteins called "master regulators" read the genome, and consequently turn genes on and off.
Monday, October 21, 2013
Cell Growth Discovery Has Implications for Targeting Cancer
The way cells divide to form new cells is controlled in previously unsuspected ways.
Monday, October 21, 2013
Discovery Could Lead to Saliva Test for Pancreatic Cancer
The disease is typically diagnosed through an invasive and complicated biopsy.
Tuesday, October 15, 2013
Tuberculosis and Parkinson’s Disease Linked by Unique Protein
UCSF researchers seek way to boost protein to fight both diseases.
Wednesday, September 11, 2013
Effects of Parkinson’s Disease Mutation Reversed in Cells
UCSF study used chemical commonly found in anti-wrinkle cream.
Friday, August 23, 2013
Dentistry School Receives $5M to Study Saliva Biomarkers
Imagine having a sample of your saliva taken at the dentist's office, and then learning within minutes whether your risk for stomach cancer is higher than normal.
Thursday, August 15, 2013
Scientists Devise Innovative Method to Profile and Predict the Behavior of Proteins
A class of proteins that are made up of multiple, interlocking molecular components, enzymes perform a variety of tasks inside each cell.
Friday, August 09, 2013
Immune System Molecule Promotes Tumor Resistance
A team of scientists has shown for the first time that a signaling protein involved in inflammation also promotes tumor resistance to anti-angiogenic therapy.
Tuesday, August 06, 2013
Deadliest Cancers May Respond to New Drug Treatment Strategy
Researchers have found a way to knock down cancers caused by a tumor-driving protein called “myc,” paving the way for clinical trials.
Monday, July 22, 2013
Brain Anomolies are Potential Biomarkers for Autism
Brain anomalies may serve as potential biomarkers for the early identification of the neurodevelopmental disorder.
Wednesday, July 10, 2013
Second Amyloid May Play a Role in Alzheimer's
The study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer's disease.
Monday, July 01, 2013
Absence of Gene Leads to Earlier, More Severe Case of Multiple Sclerosis
UCSF finding in animal study may lead to biomarker that predicts course of disease in humans.
Tuesday, June 25, 2013
Scientific News
Lemon Juice and Human Norovirus
Citric acid may prevent the highly contagious norovirus from infecting humans, scientists discovered from the German Cancer Research Center.
Signature of Microbiomes Linked to Schizophrenia
Studying microbiomes in throat may help identify causes and treatments of brain disorder.
Structural Discoveries Could Aid in Better Drug Design
Scientists have uncovered the structural details of how some proteins interact to turn two different signals into a single integrated output.
Protein Found to Play a Key Role in Blocking Pathogen Survival
Calprotectin fends off microbial invaders by limiting access to iron, an important nutrient.
Study Identifies the Off Switch for Biofilm Formation
New discovery could help prevent the formation of infectious bacterial films on hospital equipment.
How DNA ‘Proofreader’ Proteins Pick and Edit Their Reading Material
Researchers from North Carolina State University and the University of North Carolina at Chapel Hill have discovered how two important proofreader proteins know where to look for errors during DNA replication and how they work together to signal the body’s repair mechanism.
Protein Found to Control Inflammatory Response
A new Northwestern Medicine study shows that a protein called POP1 prevents severe inflammation and, potentially, diseases caused by excessive inflammatory responses.
X-ray Laser Experiment Could Help in Designing Drugs for Brain Disorders
Scientists found that when two protein structures in the brain join up, they act as an amplifier for a slight increase in calcium concentration, triggering a gunshot-like release of neurotransmitters from one neuron to another.
Team Identifies Structure of Tumor-Suppressing Protein
An international group of researchers led by Carnegie Mellon University physicists Mathias Lösche and Frank Heinrich have established the structure of an important tumor suppressing protein, PTEN.
Why We’re Smarter Than Chickens
Toronto researchers have discovered that a single molecular event in our cells could hold the key to how we evolved to become the smartest animal on the planet.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
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
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!