Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Penn study shows how misfolded proteins are selected for disposal

30.05.2014

Research has implications for understanding brain diseases caused by clumps of misshapen molecules

It's almost axiomatic that misfolded proteins compromise how cells normally function and cause debilitating human disease, but how these proteins are detected and degraded within the body is not well understood. Neurodegenerative diseases – including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), Huntington's disease, and spinocerebellar ataxias – exact a devastating toll on aging populations throughout the world.


This is a model for protein quality control by the PML-RNF4 system.

Credit: Lili Guo, Ph.D., Perelman School of Medicine, University of Pennsylvania; Molecular Cell

"Yet, there is virtually no cure for any of these diseases, and clinical trials have yielded mostly disappointing results, indicating that investigators are missing something fundamental about these diseases," says Xiaolu Yang, PhD, professor of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania. All of these diseases are caused by the accumulation of toxic misfolded proteins in different types of neurons. "However, our knowledge about how cells normally remove these proteins, an issue fundamental to understanding what goes wrong in neurodegenerative diseases, is very limited."

Yang and first author Lili Guo, PhD, who was a doctoral student in the Yang lab, identified a protein recycling pathway in mammalian cells that removes misfolded proteins. Their findings appear online today in Molecular Cell ahead of the print edition. They also demonstrated this pathway's role in protecting against neurodegenerative diseases in an animal model. Guo is now a postdoctoral fellow in another Perelman School lab.

Proteins are the work horses of the cells. They are the most abundant macromolecules, extremely versatile in their functions and critically important for virtually all biological processes. However, proteins are also highly prone to misfolding due to genetic mutations, synthetic inaccuracies, and irreparable damages. What's more, the half-life of many proteins is relatively short, from a few minutes to a few hours, necessitating their continued synthesis. As such this puts a burden on the cell to maintain quality control in the correct folding of proteins.

"This paper resolves a long-standing question in protein quality control of how misfolded proteins are precisely selected for degradation," notes Yang. "This newly described system could be a valuable target for treating neurodegenerative diseases."

Two-Staged Recycling

In any normally functioning cell, two systems maintain protein quality. First, chaperone proteins, like fingers that fold paper into origami shapes, guide amino acid chains in folding into their final, proper protein forms. Second, the recycling systems dispose of misfolded proteins and ultimately breaks them up into individual amino acids. This system involves the proteasome, a protein complex found throughout the cytoplasm and nucleus of cells. "But it is unclear how misshapen proteins are recognized and shuttled to the proteasome to be degraded. This study moves the field forward because we showed that the system is common for many types of misfolded proteins," notes Yang.

In addition to identifying the step-by-step molecular players of the system that eliminates misfolded proteins, they also defined the system's method of action. The mechanism of action is a relay system with two proteins.

The first protein, PML/TRIM19, recognizes features of misfolded proteins such as exposed water-phobic inner cores, which stick out and enhance the forming of toxic protein clumps. PML selectively interacts with misfolded proteins by recognizing this and other distinct features and tags the misfolded proteins with chains of a small protein called SUMO (small ubiquitin-like modifier). The SUMO-modified misfolded proteins are then recognized by the second protein, RNF4, which tags them with chains of another small protein called ubiquitin. The ubiquitin chain is a signal that can be recognized by the barrel-shaped proteasome, leading to the degradation of misfolded proteins.

The team then went on to demonstrate the physiological importance of the elimination system using a mouse model of spinocerebellar ataxia 1 (SCA1), a fatal neurological disorder that causes problems with movement and balance. Mutations in the ATXN1 gene cause SCA1, which involves repeated segments of the DNA building blocks cytosine (C), adenine (A), and guanine (G) that appear multiple times in a row in the gene, which encodes a tract of contiguous glutamine amino acids. Normally, the CAG segment is repeated 4 to 39 times within the gene. In SCA1, the CAG segment is repeated 40 to more than 80 times, which leads to an abnormally long ataxin-1 protein that folds into the wrong 3-dimensional shape and forms clumps within the nucleus. The team showed that a PML deficiency exacerbates both the behavioral and neuropathological defects caused by the expanded CAG repeat in the SCA1 mouse, indicating that PML normally operates to protect against neurodegeneration.

The PML protein is also involved in the formation of tumors, and that's how Yang, a cancer biologist, got involved in this type of research.

"The knowledge gained from this project now provides for the possibility of new therapeutic targets for neurodegenerative diseases. Perhaps new drugs could enhance the elimination system by increasing the action of PML or RNF4, or could inhibit the inhibitors of the SUMO and ubiquitin tagging process," says Yang

###

Other co-authors are Alex Glavis-Bloom, Michael D. Brewer, James Shorter, Aaron D. Gitler, now at Stanford Medical Center, and Benoit I. Giasson, now at the University of Florida.

The research was supported in part by grants from the National Cancer Institute (CA088868) and the National Institute of General Medical Sciences (GM060911).

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.

Karen Kreeger | Eurek Alert!

Further reports about: CAG Medicine PML amino chains diseases misfolded neurodegenerative proteasome proteins

More articles from Life Sciences:

nachricht Gene switch may repair DNA and prevent cancer
12.02.2016 | Institute for Integrated Cell-Material Sciences at Kyoto University

nachricht New method opens crystal clear views of biomolecules
11.02.2016 | Deutsches Elektronen-Synchrotron DESY

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Production of an AIDS vaccine in algae

Today, plants and microorganisms are heavily used for the production of medicinal products. The production of biopharmaceuticals in plants, also referred to as “Molecular Pharming”, represents a continuously growing field of plant biotechnology. Preferred host organisms include yeast and crop plants, such as maize and potato – plants with high demands. With the help of a special algal strain, the research team of Prof. Ralph Bock at the Max Planck Institute of Molecular Plant Physiology in Potsdam strives to develop a more efficient and resource-saving system for the production of medicines and vaccines. They tested its practicality by synthesizing a component of a potential AIDS vaccine.

The use of plants and microorganisms to produce pharmaceuticals is nothing new. In 1982, bacteria were genetically modified to produce human insulin, a drug...

Im Focus: The most accurate optical single-ion clock worldwide

Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock which attains an accuracy which had only been predicted theoretically so far. Their optical ytterbium clock achieved a relative systematic measurement uncertainty of 3 E-18. The results have been published in the current issue of the scientific journal "Physical Review Letters".

Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock...

Im Focus: Goodbye ground control: autonomous nanosatellites

The University of Würzburg has two new space projects in the pipeline which are concerned with the observation of planets and autonomous fault correction aboard satellites. The German Federal Ministry of Economic Affairs and Energy funds the projects with around 1.6 million euros.

Detecting tornadoes that sweep across Mars. Discovering meteors that fall to Earth. Investigating strange lightning that flashes from Earth's atmosphere into...

Im Focus: Flow phenomena on solid surfaces: Physicists highlight key role played by boundary layer velocity

Physicists from Saarland University and the ESPCI in Paris have shown how liquids on solid surfaces can be made to slide over the surface a bit like a bobsleigh on ice. The key is to apply a coating at the boundary between the liquid and the surface that induces the liquid to slip. This results in an increase in the average flow velocity of the liquid and its throughput. This was demonstrated by studying the behaviour of droplets on surfaces with different coatings as they evolved into the equilibrium state. The results could prove useful in optimizing industrial processes, such as the extrusion of plastics.

The study has been published in the respected academic journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).

Im Focus: New study: How stable is the West Antarctic Ice Sheet?

Exceeding critical temperature limits in the Southern Ocean may cause the collapse of ice sheets and a sharp rise in sea levels

A future warming of the Southern Ocean caused by rising greenhouse gas concentrations in the atmosphere may severely disrupt the stability of the West...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Symposium on Climate Change Adaptation in Africa 2016

12.02.2016 | Event News

Travel grants available: Meet the world’s most proficient mathematicians and computer scientists

09.02.2016 | Event News

AKL’16: Experience Laser Technology Live in Europe´s Largest Laser Application Center!

02.02.2016 | Event News

 
Latest News

LIGO confirms RIT's breakthrough prediction of gravitational waves

12.02.2016 | Physics and Astronomy

Gene switch may repair DNA and prevent cancer

12.02.2016 | Life Sciences

Using 'Pacemakers' in spinal cord injuries

12.02.2016 | Medical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>