Researchers Elucidate Way Lungs Fight Bacteria And Prevent Infection
Actor and pancreatic cancer patient Patrick Swayze’s recent hospitalization with pneumonia as a result of his compromised immune system underscores the sensitivity of the lungs: many patients die from lung complications of a disease, rather than the disease itself.
Lungs are delicate and exposed to the environment, almost like an open wound. Consequently, the body has developed an elaborate immuno-defense system to combat inhaled pathogens and bacteria in a healthy individual, this system effectively blocks hundreds of potentially sickening assaults daily.
It works like this: airway epithelial cells initiate an immune response to inhaled bacteria by signaling for white blood cells to move from the bloodstream into the lungs and airway to fight potential infection.
For the first time, researchers at Columbia University Medical Center have demonstrated that this signaling cascade includes the activation of epithelial proteases, a type of enzyme capable of opening the junctions between the cells in the airway mucosa, to enable the white blood cells to get through to the site of the infection. The opening of these junctions is initiated by a change in calcium levels.
The work by Drs. Jarin Chun and Alice Prince in the Departments of Pharmacology and Pediatrics at Columbia’s College of Physicians and Surgeons was published Jan. 22, 2009 in the journal Cell Host & Microbe.
Getting white blood cells to the site of an infection, however, is often a double-edged sword. On the one hand, having as many white blood cells as possible at the site of an infection is beneficial, but on the other hand too many white blood cells can lead to excessive inflammation, interfering with breathing and damaging the airways.
Cystic fibrosis is one disease where this work might have particular import, Dr. Chun says. People with cystic fibrosis possess an abnormal gene that causes normal mucus to become thick and sticky, leaving the lung more prone to infection and inflammation, while still killing infection-causing bacteria.
The findings, in mice, demonstrate a way to inhibit proteases and restrict the junctions between cells in the airway mucosa, meaning that fewer white blood cells can get into the airway causing less inflammation.
Thus, epithelial proteases could be an important target to control inflammation in the lung, and could serve as the basis for the development of novel drugs to help the human body get the optimal number of white blood cells to an infection site without letting inflammation spiral out of control.
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia’s College of Physicians & Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States. For more information, please visit http://www.cumc.columbia.edu.
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Journal Articles Underscore The Importance Of Air Bags/Seat Belts In Preventing Spine Fractures
An article and accompanying editorial published in the February 2009 issue of Journal of Neurosurgery: Spine provide compelling evidence that the combination of air bags and seat belts affords the best protection against spine fractures sustained in motor vehicle crashes. This research examined the records of more than 20,000 crash victims age 16 and older admitted to Wisconsin hospitals after car or truck crashes from 1994 to 2002. The article, “The continued burden of spine fractures after motor vehicle crashes” and the editorial are posted online at http://thejns.org/toc/spi/current.
Article authors are Marjorie C. Wang, MD, MPH, Frank Pintar, PhD, Narayan Yoganandan, PhD, and Dennis J. Maiman, MD, PhD, Department of Neurosurgery, Medical College of Wisconsin, Milwaukee. The editorial was written by Charles H. Tator, MD, PHD, Division of Neurosurgery, Toronto Western Hospital and University of Toronto.
In 2007, there were over 6 million motor vehicle accidents in the United States. Nearly 2.5 million of those accident victims were injured and more than 41,000 lost their lives. “Motor vehicle accidents are the leading cause of spinal cord injury (SCI) in the United States for people age 65 and younger and spine fractures are a significant cause of morbidity and mortality,” said Dr. Wang. A spine fracture is a break in one or more of the bones of the spine (vertebrae in the back or neck). Spine fractures can lead to a complete SCI, which may result in some degree of paralysis or even death. Of the 2,530 patients with spine factures analyzed in this study, 64 died in the hospital.
“I commend Dr. Wang and her group for performing this extensive, labor-intensive epidemiological study of motor vehicle crash victims. This research offers an invaluable assessment of air bags and seat belts two safety measures that when used together show evidence of decreasing the risk of these traumatic and often devastating injuries,” stated Dr. Tator.
Dr. Wang and her team analyzed the data and correlated the incidence of spine fractures with air bag and seat belt usage. Of the 29,860 motor vehicle crash hospital admissions, a data group of 20,276 drivers and front seat passengers was analyzed. This group met the following criteria: drivers or front seat passengers age 16 or older with complete ICD-9-CM and air bag/seat belt data who were not ejected from the vehicle. Key research findings include:
– Use of a seat belt and an air bag together was associated with a decreased risk of a spine fracture, including more severe fractures.
– Only 14 percent of the drivers and front seat occupants involved in Wisconsin motor vehicle crashes between 1994 and 2002 were protected by the combination of air bags and seat belts, although this number increased from 1994 to 2002.
– An alarming 38 percent of these crash victims were not wearing seat belts.
– There were 2,530 spine fractures (12.5 percent) identified among the 20,276 hospital admissions: 1,067 cervical fractures, 565 thoracic fractures, and 1,034 lumbosacral fractures. Eighty-two patients (8 percent) with a cervical fracture also had a thoracic and/or a lumbosacral fracture. Fifty-four patients with a thoracic fracture, (10 percent) also had a lumbosacral fracture. Eight percent of these were classified as severe.
– Use of an air bag alone was associated with an increased risk of a severe thoracic spine fracture.
The Wisconsin Department of Transportation has acknowledged that speeding and alcohol are two principal crash factors, as has the National Highway Traffic Safety Administration (NHTSA). “An important step would be to build a national coalition which advocates for reduced speed limits, mandatory installation of air bags, enforcement/use of seat belts, and deployment of electronic data record systems (EDRs) in all cars and trucks,” remarked Dr. Tator.
“It is possible that improved imaging techniques contributed to an increase in the diagnosis of minor spine fractures,” stated Dr. Wang. “However, in our study, patients with spine fractures had longer hospital stays and higher Injury Severity Scores, suggesting that patients with motor vehicle-related spine fractures are more severely injured. Additional research including improved classification of spine fractures will help further clarify the overall public health impact of these injuries. In conclusion, state and national resources should be dedicated towards increasing the use of both air bags and seat belts,” concluded Dr. Wang.
Unrestricted research support was provided by EBI Medical, Inc., and Abbott Spine. Dr. Wang receives unrelated research support from the Robert Wood Johnson Foundation.
Founded in 1944, the Journal of Neurosurgery, the official scientific journal of the AANS, has been recognized by neurosurgeons and related medical specialists worldwide for its authoritative and cutting-edge clinical articles, laboratory research papers, case reports, literature reviews, technical notes, book reviews, and more. Each successive editor-in-chief from Louise Eisenhardt to the current editor, John A. Jane, Sr. has played a key role in shaping a publication that stays on the cutting edge of a constantly advancing specialty. Each manuscript is reviewed by at least three editorial board members, in addition to the Editor and occasionally one or more expert reviewers.
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Infants Draw On Past To Interpret Present, Understand Other People’s Behavior
The old real estate maxim “location, location, location” also plays a role in how infants learn to understand the ambiguous actions and behavior of other people.
University of Washington psychologists have learned that 10-month-old infants use their prior exposure and understanding of familiar actions by a person to unravel novel actions. However, this ability is limited by the location in which the new action is performed.
“Infants’ understanding of and exposure to familiar actions can boost their understanding of ambiguous action sequences. Their ability to draw on the past to interpret the present represents an important advance in their developing understanding of other people’s behavior,” said Jessica Sommerville, a UW assistant professor of psychology who is also affiliated with the university’s Institute for Learning and Brain Sciences.
Although the research was conducted on infants, she believes the findings apply across all ages.
“Providing advance information about the ultimate goal or objective of what you are trying to teach before delivering the actual content helps people learn. College instructors and school teachers are often instructed to highlight the goal of a lecture, course or lesson in advance to facilitate learning. Our work demonstrates that this phenomenon is present in infancy. Advance information about an individual’s goals helps infants understand and learn from another person’s actions within the first year of life.”
UW researchers conducted two experiments to test how well infants can use prior information.
In the first, 48 typically developing infants took part in a two-phase experiment. During the first phase, infants received information about which of two objects a research assistant desired. Across five trials, infants consistently saw the assistant reach for, grasp and pick up one of two plastic toys (a green frog or a red fish) while saying “Wow!” For the second phase, the infants were randomly divided into same- and different-room conditions.
Half the babies stayed in the same room, but the setup was slightly different. This time the frog and fish each sat out of reach of the assistant on top of distinctly different colored cloths. Infants watched as the assistant used the cloth supporting the toy that she had previous desired to retrieve the target toy. Infants’ visual attention to these events was measured, and after infants’ attention declined they participated in novel test trials. The test trials varied. Some of them featured a change in the toy the assistant went after while others featured a change in the cloth that was used by the assistant. The procedure was the same for the different-room group, except these infant receive the second phase in another room.
Prior research suggests that 10-month-old infants do not spontaneously recognize the meaning behind the cloth-pulling sequence. They apparently don’t understand that a person pulls the cloth to retrieve the desired out-of-reach toy. The UW researchers wanted to know if the infants could use information from the first phase to identify the assistant’s intention in the second phase. They used infants’ visual attention to the novel test events to gauge infants’ understanding of the cloth-pulling sequence. Infants in the same-room condition showed heightened attention to a change in the toy that the assistant retrieved rather than a change in the cloth she used. This suggests that the infants understood that the assistant pulled the cloth in order to obtain her desired toy, and were surprised when her intention changed, according to Sommerville.
In contrast, infants in the different-room condition did not distinguish between the two test events.
The second experiment was virtually identical to the first, except half of the infants were taken out of the testing room for 30 seconds after the first phase, matching the time it took the different-room group to switch rooms in the first experiment. Then they returned to the same room. This time both groups of infants looked significantly longer at the change in the toy the assistant pulled with the cloth.
“Our findings suggest that infants use prior information about a person’s goals and desires to understand novel or ambiguous action. But they also suggest that infants may be limited in their ability to generalize this information to new contexts at 10 months of age,” said Sommerville. “Alternately, infants may be able to generalize information across a change in context, but they may be more reluctant to generalize expectations about others’ behavior than are older children or adults.”
She said the research also has practical applications that parents could use when they want to teach their children something.
“Our work suggests that children’s learning may benefit if they are provided with information about the desired end result of a game or activity before starting it. For example, if a parent wants to show a child how to operate a jack-in-the-box it might be helpful to show the desired outcome (the jack popped out of the box), and then demonstrate the step that are necessary to achieve that result.”
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Article adapted by Medical News Today from original press release.
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Co-author of the findings, which are published on-line in the journal Developmental Science, is Catharyn Crane, a UW psychology doctoral student. The research was funded by the UW’s Royalty Research Fund.
Source: Joel Schwarz
University of Washington
Smokers Are Twice As Likely To Kick The Habit If They Use A Support Group Rather Than Trying To Give Up Alone
Researchers from the UK Centre for Tobacco Control Studies led by Dr Linda Bauld at Bath, along with colleagues from the University of Glasgow, have published research in the February issue of Addiction journal comparing the success and cost-effectiveness of two types of stop smoking support services offered by the NHS. These are community-based group stop smoking support and one-to-one support provided in a pharmacy setting.
The study, funded by the Glasgow Centre for Population Health, NHS Greater Glasgow and Clyde and Health Scotland, found that more than a third of smokers using support groups quit smoking after four weeks; almost double the proportion of those using a pharmacy-based support scheme to help them quit.
Dr Linda Bauld said: “Smoking is the leading cause of preventable illness and death in the UK, and the single biggest cause of inequalities in health.
“These findings agree with previous research which shows that smokers who used a support group were more likely to quit. But we know that only a very small proportion of smokers using NHS stop smoking services in the UK use this form of help.
“We need to get the message across that group support, combined with stop smoking medications, works well for many people.
“However, we found that both types of service in Glasgow are reaching and treating smokers from disadvantaged areas in substantial numbers, which is extremely encouraging and will contribute to efforts to reduce inequalities in health.”
Pharmacy-based support is available in over 200 pharmacies across Glasgow and at the time of the study treated over 12,000 smokers per year. The service includes one-to-one behavioural support for up to 12 weeks, with each session usually lasting from five to 15 minutes; this support is combined with a direct supply of Nicotine Replacement Therapy (NRT), usually in the form of patches.
The second service assessed in the study involved community-based group counselling and lasts for seven weeks, with each session lasting around an hour. A trained advisor is able to give vouchers for NRT for collection at pharmacies and advise on other types of smoking cessation medicine which the client can then get from their GP.
After the course of group counselling sessions has ended, smokers can receive ongoing support and medication from their pharmacy for a further five weeks. At the time of the study, this method was used by 1,700 smokers per year in Glasgow.
Early results from the study’s economic analysis suggest that the pharmacy based service is less costly to deliver than group support. Overall though, the economic analysis found that both types of service are cost-effective.
Professor Carol Tannahill, Director of the Glasgow Centre for Population Health, said: “Many smokers feel that they have to manage to give up smoking on their own, yet there are now a range of services available to support smokers to quit. This research sets out to examine how effective different services are, and what factors may influence outcomes.”
The next stage of the study in Glasgow involves the collection and analysis of one year outcomes from the smokers who participated in this initial study.
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Article adapted by Medical News Today from original press release.
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The University of Bath is one of the UK’s leading universities, with an international reputation for quality research and teaching.
Source: Vicky Just
University of Bath
Discovery Of A Key Protein Regulator Of Inflammation And Cell Death
Reporting in the journal Nature, researchers led by Emad Alnemri, Ph.D., professor of Biochemistry and Molecular Biology in the Kimmel Cancer Center at Jefferson, discovered a key protein component involved in inflammation.
The protein, AIM2 (absent in melanoma 2), is involved in the detection and reaction to dangerous cytoplasmic DNA that is produced by infection with viral or microbial pathogens, or by tissue damage. AIM2 also appears to be a tumor suppressor, and its inactivation may play a role in the development of cancer, according to Dr. Alnemri.
AIM2 belongs to a class of proteins called inflammasomes, which are multi-protein complexes that play major roles as guardians against both viral and bacterial infections. Inflammasomes also detect dangerous self-molecules associated with tissue damage.
According to Dr. Alnemri, when cells are infected with pathogens, AIM2 senses the presence of the pathogen’s DNA in the cytoplasm. It then binds to the foreign DNA and causes a rapid inflammatory reaction that sends a danger signal alerting the body to the invading pathogen.
When AIM2 binds to the foreign DNA, it recruits a cytoplasmic protein called ASC. ASC and AIM2 then work together to activate caspase-1, a cysteine protease involved in the production of interleukin1beta and other inflammatory cytokines that cause inflammation.
“Researchers have long sought this elusive protein that senses the presence of DNA in the cytoplasm, which is associated with pathogenic infection or the escape of undigested self-DNA into the cytoplasm,” Dr. Alnemri said. “We not only identified the key protein in this process, but also discovered how this protein reacts to DNA and causes inflammation. The inflammatory response triggered when AIM2 binds to foreign DNA in the cytoplasm is the body’s way of alerting other systems that there is a danger present in the cell.”
According to Dr. Alnemri, the activation of AIM2 also leads to death of the infected cells, which removes the damaged cells from the body. This prevents the pathogen from replicating in the cells and spreading to other parts of the body. The fact that AIM2 can induce cell death raises the possibility that AIM2 might function as a tumor suppressor, by killing cells with damaged DNA before they transform into cancers. Inactivation of AIM2 thus might confer a growth advantage to abnormal cells and lead to the development of cancer.
“The discovery and understanding of the AIM2 inflammasome should enable scientists to design novel therapeutics that modulate its activity,” Dr. Alnemri said. “Such therapeutics may be useful for the treatment of nucleic acid-dependent pathogenic and autoimmune diseases, such as arthritis and systemic lupus erythematosus,” Dr. Alnemri said.
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Article adapted by Medical News Today from original press release.
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Source: Emily Shafer
Thomas Jefferson University
The Decoding Of The Language Of Memory Cells Impacts On Vaccination, Cancer Research
When an infection attacks, the body’s immune system sounds the alert, kills the invading germs and remembers the pathogen to protect against contracting the same type of infection again. Exactly how immunological memory develops is a mystery just beginning to be unveiled by Emma Teixeiro, PhD, in an article published in the Jan. 23 issue of the journal Science.
The key finding is that a distinct program generates the memory cells that protect an individual against re-infection. This current work uncovers some of the language that is necessary to start this program, said Teixeiro, assistant professor of molecular microbiology, immunology and surgery at the University of Missouri School of Medicine.
Teixeiro cites vaccination as the most practical example of how to generate cells that remember infections. With a single shot, the body is infected with a small dose of a pathogen, so the next time the body is exposed, it immediately recognizes the invader and fights it off, preventing disease.
“When the human body is infected, T cells recognize the pathogen with a specific receptor and kill the infection,” Teixeiro said. “But once the infection has been cleared, a small number of cells survive. These are the memory T cells.”
Teixeiro’s lab used a mouse model to test how communication inside a T cell would affect a body’s ability to fight infection. Two groups of mice – some with normal T cells and others with a mutation in their pathogen receptor – were infected with listeria monocytogenes, a bacterium often associated with food-borne illness in humans. Both groups of mice fought off the infection equally well, but those with the cell mutation were not able to generate memory T cells to protect against future infection due to a disruption in certain signals within the cell.
“A person with this cell mutation would not develop memory T cells. If we knew what was necessary to generate these memory cells, we would not need to worry about fighting the same infection over and over again,” Teixeiro said, noting a direction for continued research. “We are currently figuring out which signals are important for memory generation and protection. This is important for improving vaccines and tumor immunotherapies.”
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Article adapted by Medical News Today from original press release.
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Teixeiro, a native of Spain, began this research during her post-doctoral study in the department of biomedicine at University Hospital in Basel, Switzerland. Since she arrived at the University of Missouri in January 2008, her research has been funded in part by the university’s mission enhancement program.
Science is the world’s largest paid-circulation peer reviewed general science journal in the world. Teixeiro’s article “Different T Cell Receptor Signals Determine CD8 Memory Versus Effector Development,” is published in the journal’s January 23, 2009 issue.
Source: Natalie Fieleke
University of Missouri-Columbia
Schizophrenic Patients’ Frozen Faces Harm Social Interactions
Non-verbal communication, in the form of facial expressions, may be impaired in people with schizophrenia. Researchers writing in BioMed Central’s open access journal Behavioral and Brain Functions have shown that deficits in non-verbal expressivity in schizophrenia are linked to poor social skills and an unawareness of the thoughts and intentions of others.
Martin Brüne from the University of Bochum, Germany, led a team of researchers who used interviews and psychological tests to gauge whether reduced nonverbal expressivity could be linked to patients’ social-cognitive impairments and poor social competence. He said “We were able to show that patients with schizophrenia were reduced in their non-verbal expressivity during an interview that explored psychopathological symptoms and subjective factors of distress. Moreover, we found that patients with the lowest level of nonverbal expressivity performed more poorly on a test that tapped into the comprehension of others’ minds than patients whose nonverbal expressivity during interviews was within the range of healthy controls.”
The ability to “mentalise”, to accurately imagine the thoughts, feelings or intentions that another person is experiencing, is known to be impaired in schizophrenic patients. Brüne and his colleagues have previously shown that this impairment is associated with poor social skills. He said, “By showing that a link exists between non-verbal expressivity and the inability to mentalise, we hope to better specify the factors that actually guide and motivate patients’ interpersonal nonverbal behaviour”.
Brüne speculates that poor mentalising abilities contribute to patients’ reduced use of the nonverbal behaviours that invite and sustain social interaction in conversation, and that reduced signals of this type then contribute, in part, the difficult and unappealing nature of conversation with schizophrenic patients.
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Article adapted by Medical News Today from original press release.
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Notes:
1. Linking non-verbal expressivity with social competence and “mentalising” in patients with schizophrenia spectrum disorders
Martin Brüne, Mona Abdel-Hamid, Claudia Sonntag, Caroline Lehmkämper and Robyn Langdon
(in press)
Article available at journal website: http://www.behavioralandbrainfunctions.com/
All articles are available free of charge, according to BioMed Central’s open access policy.
2. Behavioral and Brain Functions is an Open Access, peer-reviewed, online journal that encompasses all aspects of neurobiology where the unifying theme is behavior or behavioral dysfunction. Behavioral and Brain Functions is aimed at the scientific community interested in behavioral and cognitive neuroscience, investigating the psychological, computational, and neuroscientific bases of normal and abnormal behavior including the mind. The interdisciplinary nature of the field covers developments in human and animal behavioral science, neuroscience, neuropsychology, cognitive psychology, neurobiology, linguistics, computer science, and philosophy.
3. BioMed Central (http://www.biomedcentral.com/) is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector.
Source: Graeme Baldwin
BioMed Central
Clues To Aging Process From The Breakdown Of Barriers In Old Cells
Like guards controlling access to a gated community, nuclear pore complexes are communication channels that regulate the passage of proteins and RNA to and from a cell’s nucleus. Recent studies by researchers at the Salk Institute for Biological Studies offer new insights about the pores’ lifespan and how their longevity affects their function.
Their findings, reported in the Jan. 23 issue of Cell, may provide clues to one of the most enduring questions of biology: how and why cells age. They also offer a new, promising avenue of investigation for scientists pursuing intervention strategies for neurodegenerative diseases.
“We still have a very poor understanding of the mechanisms behind cell aging. It has been known for some time that the gene expression profile of an aging cell changes and somehow is linked to age-related diseases, but no one really knows why. Our work could provide an explanation for why we observe age-dependent defects in cells,” says Martin Hetzer, Ph.D., an assistant professor in the Salk’s Molecular and Cell Biology Laboratory.
Made up of 30 different proteins, nuclear pore complexes assemble during cell division and penetrate the membrane separating the nucleus from the cytoplasm. Their job is traffic control on the world’s busiest thoroughfare: Each one mediates approximately 1,000 transport events a second. Since nuclear pore complexes are as essential to nondividing cells as they are to dividing ones, the Salk team wanted to determine what happens to them over time. Do they turn over in nondividing cells, or do they remain in place for the life of the cell?
Because most of the cells in our body are not actively dividing, the answer would have implications for aging and age-related diseases. “Many of the neurons in the cortex area of the brain are as old as we are; they are nondividing for a very long time,” explains Hetzer.
Approximately half the proteins in the nuclear pore complex make up the central scaffold, or core, while the other, peripheral proteins attach to the scaffold. Using C. elegans, a tiny roundworm that as an adult consists entirely of nondividing cells, Hetzer and his group found that while the peripheral proteins are continually exchanged, the proteins comprising the scaffold remain in place for the life of the cell.
Although the scaffold proteins are detectable, their genes are no longer active. The same held true in nondividing rat neurons. “If proteins are there, but transcripts of the information making the protein are no longer there, they have to be very stable,” says Hetzer, noting that whereas most proteins turn over in minutes or hours, the ones comprising the scaffold in the nuclear pore complex remained intact for the entire lifespan of an organism. “We discovered one of the most stable structures in our cells.”
“It’s a novel concept,” adds first author Maximiliano A. D’Angelo, Ph.D., a research associate in the Hetzer lab. “No one really saw a structure that would last for the entire life of the cell.”
Hetzer and his group then set out to ascertain how these stable proteins hold up over time. Since one of the functions of the nuclear pore complex is to set a permeability barrier between the nucleus and cytoplasm, the researchers developed a reporting system that would scrutinize the barriers to see how efficient they were at excluding inappropriate molecules, much as security auditors keep tabs on airport baggage screeners’ ability to detect and block contraband.
What they found was that in aging cells, one of the proteins composing the scaffold structure becomes damaged, and the permeability barrier deteriorates; molecules that should be restricted to the cytoplasm invade the nucleus.
“Because some cells live for a long time, the accumulation of damage in the long-lived nuclear pore complexes can impair their function and have important consequences for cell homeostasis and survival,” says D’Angelo. “It may also play a significant role in the aging process.”
In particular, a protein called tubulin, which is strictly a cytoplasmic protein, shows up as long filaments that co-opt a large part of the nucleus. For more than 100 years, pathologists had been aware of these filaments, but their origins were unknown. Associated with several neurodegenerative diseases, including Parkinson’s, the filaments are found particularly in the substantia nigra of many Parkinson’s patients, the part of the brain that is involved in dopamine production and that is affected by the condition.
Hetzer’s team hypothesizes that it is the age-dependent defects in the scaffold proteins that undermine the nuclear permeability barrier. “We predict that when the permeability barrier is impaired, molecules are either lost from the nucleus or can leak into the nucleus and thereby change gene expression profiles,” says Hetzer. “This could be a general aging mechanism, and it provides an explanation for the origin of these filaments, which have been known by pathologists for a long time.”
By finding ways to prevent or reverse the leakage, the Salk researchers may be on course to identify novel approaches to treating these perplexing, devastating, and costly conditions.
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Article adapted by Medical News Today from original press release.
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In addition to Hetzer and D’Angelo, postdoctoral researcher Marcela Raices, Ph.D., and doctoral candidate Siler H. Panowski of Dr. Andrew Dillin’s laboratory at the Salk Institute contributed to this study. The research was carried out with funding from the NIH.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health, and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
Source: Gina Kirchweger
Salk Institute
Leaky Membranes: Another Sign Of Old Age
As parts of us age, even the membrane bound nuclei , which house the genetic instructions for life that are “written” in our DNA, begin to show considerable wear and tear, suggests a new report in the January 23rd issue of the journal Cell, a Cell Press publication. The nuclear pore complexes that normally act as gatekeepers–selectively importing and exporting the molecular ingredients for life to and from the nucleus–begin to break down and spring leaks.
That’s because some of the 30 or so nucleoporin proteins that make up those complexes can’t be replaced once cells stop dividing, they found.
” These proteins are unusually stable,” said Martin Hetzer of the Salk Institute for Biological Studies. “Most proteins turnover within minutes or hours. These last the entire life span of the cell,” a period that can in some cases be decades. In fact, he said, many cells in the body do not actively divide most of the time, and that lack of cell division is particularly dramatic for cells such as muscle and neurons.
Earlier studies had shown that some components of the nuclear pore complexes are very dynamic while others hang around throughout the cell cycle, getting replaced only when cells split into two daughter cells, Hetzer explained. His team wondered what that meant for cells that had stopped dividing.
They now report that the scaffold nucleoporins are extremely stable and do not exchange once they are incorporated into the nuclear membrane, persisting for the entire life span of a differentiated cell. In those cells, the nuclear pore complexes deteriorate with time, eventually losing nucleoporins that are critical for maintaining the pore diffusion barrier. Strikingly, they found that nuclei of old rat neurons containing deteriorated nuclear pore complexes become increasingly permeable.
Cells are usually very efficient at getting rid of old or damaged proteins and replacing them with new copies, Hetzer said, but it seems they have no way to replace the most stable components of the nuclear pore complexes. He suspects that’s because the pores are not only essential for molecular transport, but they are also structural components of the double lipid layer that is the nuclear membrane. If those gated holes are lost, the membrane collapses, he said.
” How do you replace a bridge while transport is happening?” he asked. “It’s not possible.”
Even if most of the 100s to 1000s of pores on any given cell nucleus are in decent shape and functioning, damage to a few can turn the nuclear membrane into a permeable barrier, allowing leakage of the wrong molecules in or out of the nucleus. This process might explain a phenomenon first described more than 100 years ago: that the nuclei of brain and other tissues can sometimes accumulate filaments with age. Those filaments often tend to show up in Parkinson’s and other neurodegenerative disorders, Hetzer said.
His team now reports that tubulin, proteins that make up the microtubule filaments normally found only out in the cytoplasm, accumulate in nuclei with such leaky pores. That discovery raises the intriguing possibility that defective pores may be involved in the development of human diseases, the researchers said, a notion they intend to explore by examining healthy and diseased human brain tissue.
” Our finding that nuclear ‘leakiness’ is dramatically accelerated during aging and that a subset of nucleoporins is oxidatively damaged in old cells suggests that the accumulation of damage at the nuclear pore complex might be a crucial aging event,” Hetzer’s team concludes.
Once they have a better understanding of what happens to those pores in normal aging and neurodegenerative disease, perhaps there may be some way to fix the problem, he said. For instance, if certain proteins tend to be the ones that “go,” they might be replaced in some way. Alternatively, if they can determine what it is that goes awry after those pores begin to leak, there may be ways to intervene at the secondary level as well.
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Article adapted by Medical News Today from original press release.
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The researchers include Maximiliano A. D’Angelo, Marcela Raices, Siler H. Panowski, and Martin W. Hetzer, at the Salk Institute for Biological Studies, Molecular and Cell Biology Laboratory, La Jolla, CA.
Source: Cathleen Genova
Cell Press
Leaky Membranes: Another Sign Of Old Age
As parts of us age, even the membrane bound nuclei , which house the genetic instructions for life that are “written” in our DNA, begin to show considerable wear and tear, suggests a new report in the January 23rd issue of the journal Cell, a Cell Press publication. The nuclear pore complexes that normally act as gatekeepers–selectively importing and exporting the molecular ingredients for life to and from the nucleus–begin to break down and spring leaks.
That’s because some of the 30 or so nucleoporin proteins that make up those complexes can’t be replaced once cells stop dividing, they found.
” These proteins are unusually stable,” said Martin Hetzer of the Salk Institute for Biological Studies. “Most proteins turnover within minutes or hours. These last the entire life span of the cell,” a period that can in some cases be decades. In fact, he said, many cells in the body do not actively divide most of the time, and that lack of cell division is particularly dramatic for cells such as muscle and neurons.
Earlier studies had shown that some components of the nuclear pore complexes are very dynamic while others hang around throughout the cell cycle, getting replaced only when cells split into two daughter cells, Hetzer explained. His team wondered what that meant for cells that had stopped dividing.
They now report that the scaffold nucleoporins are extremely stable and do not exchange once they are incorporated into the nuclear membrane, persisting for the entire life span of a differentiated cell. In those cells, the nuclear pore complexes deteriorate with time, eventually losing nucleoporins that are critical for maintaining the pore diffusion barrier. Strikingly, they found that nuclei of old rat neurons containing deteriorated nuclear pore complexes become increasingly permeable.
Cells are usually very efficient at getting rid of old or damaged proteins and replacing them with new copies, Hetzer said, but it seems they have no way to replace the most stable components of the nuclear pore complexes. He suspects that’s because the pores are not only essential for molecular transport, but they are also structural components of the double lipid layer that is the nuclear membrane. If those gated holes are lost, the membrane collapses, he said.
” How do you replace a bridge while transport is happening?” he asked. “It’s not possible.”
Even if most of the 100s to 1000s of pores on any given cell nucleus are in decent shape and functioning, damage to a few can turn the nuclear membrane into a permeable barrier, allowing leakage of the wrong molecules in or out of the nucleus. This process might explain a phenomenon first described more than 100 years ago: that the nuclei of brain and other tissues can sometimes accumulate filaments with age. Those filaments often tend to show up in Parkinson’s and other neurodegenerative disorders, Hetzer said.
His team now reports that tubulin, proteins that make up the microtubule filaments normally found only out in the cytoplasm, accumulate in nuclei with such leaky pores. That discovery raises the intriguing possibility that defective pores may be involved in the development of human diseases, the researchers said, a notion they intend to explore by examining healthy and diseased human brain tissue.
” Our finding that nuclear ‘leakiness’ is dramatically accelerated during aging and that a subset of nucleoporins is oxidatively damaged in old cells suggests that the accumulation of damage at the nuclear pore complex might be a crucial aging event,” Hetzer’s team concludes.
Once they have a better understanding of what happens to those pores in normal aging and neurodegenerative disease, perhaps there may be some way to fix the problem, he said. For instance, if certain proteins tend to be the ones that “go,” they might be replaced in some way. Alternatively, if they can determine what it is that goes awry after those pores begin to leak, there may be ways to intervene at the secondary level as well.
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Article adapted by Medical News Today from original press release.
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The researchers include Maximiliano A. D’Angelo, Marcela Raices, Siler H. Panowski, and Martin W. Hetzer, at the Salk Institute for Biological Studies, Molecular and Cell Biology Laboratory, La Jolla, CA.
Source: Cathleen Genova
Cell Press
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