(Press-News.org) Contact information: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Breaking the brain clock predisposes nerve cells to neurodegeneration
Findings point to possible ways to fight some age-related diseases
PHILADELPHIA - As we age, our body rhythms lose time before they finally stop. Breaking the body clock by genetically disrupting a core clock gene, Bmal1, in mice has long been known to accelerate aging , causing arthritis, hair loss, cataracts, and premature death.
New research now reveals that the nerve cells of these mice with broken clocks show signs of deterioration before the externally visible signs of aging are apparent, raising the possibility of novel approaches to staving off or delaying neurodegeneration – hallmarks of Parkinson's and Alzheimer's diseases.
Erik Musiek, M.D., Ph.D., who was a postdoctoral fellow in the lab of Garret FitzGerald, M.D., director of the Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, took on this project four years ago. Musiek, now an assistant professor at Washington University, completed this line of research over the last two years in the lab of David Holtzman, M.D., also at WashU.
The Penn-WashU team found that the expression of certain clock genes, including Bmal1, plays a fundamental role in delaying emergence of age-related signs of decay in the brain. The clock proteins appear to do this by protecting the brain against oxidative stress – a process akin to rusting – that is normally controlled by enzymes that degrade harmful forms of oxygen generated in the course of normal metabolism. Their findings appear this week in the Journal of Clinical Investigation.
"I had lunch with Garret four years ago when I was a resident in neurology at Penn and this led me to work in his lab," recalls Musiek. "He had studied oxidative stress in cells and the lab was actively pursuing the role of the molecular clock in cardiovascular and metabolic function. However, he hadn't studied the brain nor the role of the clock as a regulator of oxidative stress. Others had connected the clock to signs of aging, but hadn't focused on the brain - it seemed like an opportunity to pursue."
They found, to their surprise, that inflammation – reflected by activation of astrocytes – brain cells involved in this type of response, among other functions -- was marked in young mice in which the clock was broken by deleting Bmal1. This anticipated even more marked changes in brain pathology as the mice aged, including declines in how parts of the brain connected to each other and degenerative features in nerve-cell anatomy – all characteristic of Parkinsons and Alzheimer's disease in humans.
"When we saw this, we knew we were on to something," notes Musiek.
Further experiments revealed that these effects were not restricted to disrupting the function of Bmal1, but also occurred when genes – Clock and Npas2 – with which Bmal1 works in tandem, were both removed. By contrast, deletion of other genes in the clock apparatus had no such effect.
As for mechanism, the exaggerated rusting, or oxidation, was key. Expression of several antioxidant enzymes, which normally keep oxidant stress in check are themselves controlled by clock proteins, and thus were depleted when the clock was broken. Musiek and his colleagues found evidence that inflammation and the attendant oxidant stress were both increased in the brains of the mutant mice.
Experimental drugs are beginning to emerge that may retain waning rhythms driven by the molecular clock. "Erik's studies raise the intriguing possibility of novel therapeutic approaches to delaying the progress of age-related diseases, perhaps not only those related to the brain, as suggested by the present studies, but also in other systems, such as cardiometabolic function," says FitzGerald.
In a final twist, the Penn-WashU team pinned the neuroprotective role of the body clock to clock genes in neurons and astrocytes, rather than changes in whole-animal circadian rhythms. By selectively deleting Bmal1 in these cell types, they found that the inflammatory aspects of astrocytes, neurodegeneration, and hallmarks of oxidative stress and inflammation seen when Bmal1 was missing in all cells of the body was recapitulated.
"Our findings indicate that the protein complex of BMAL1 with CLOCK or NPAS2, in addition to, or perhaps intrinsic, to the complex's internal body-clock function, regulates protection of the brain from inflammation and oxygen free-radical induced damage. This dynamic system connects impaired clock-gene function to neurodegeneration for the first time" says Musiek.
INFORMATION:
This study was supported by the National Institute of Neurological Disorders and Stroke and the National Heart, Lung, and Blood Institute (K08NS079405, R25NS065745, HL097800, P01NS074969, P30NS057105, NS056125)
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 16 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 $398 million awarded in the 2012 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 2012, Penn Medicine provided $827 million to benefit our community.
Breaking the brain clock predisposes nerve cells to neurodegeneration
Findings point to possible ways to fight some age-related diseases
2013-11-25
ELSE PRESS RELEASES FROM THIS DATE:
Dysfunctional mitochondria may underlie resistance to radiation therapy
2013-11-25
Dysfunctional mitochondria may underlie resistance to radiation therapy
New role discovered for gene
The resistance of some cancers to the cell-killing effects of radiation therapy may be due to abnormalities in the mitochondria – the cellular structures responsible ...
Archaeological discoveries confirm early date of Buddha's life
2013-11-25
Archaeological discoveries confirm early date of Buddha's life
Evidence found at world's earliest Buddhist shrine in Nepal
WASHINGTON—Archaeologists working in Nepal have uncovered evidence of a structure at the birthplace of the Buddha dating to the sixth century B.C. ...
Study shows marijuana's potential for treating autoimmune disorders
2013-11-25
Study shows marijuana's potential for treating autoimmune disorders
Research shows how MicroRNA affected by THC
A new study from researchers at the University of South Carolina provides evidence that THC (tetrahydrocannabinol), a principal ingredient ...
Offshore pockmarks, Wax Lake Delta, Cabo de Gata, the Siberian Traps: Geology covers the world
2013-11-25
Offshore pockmarks, Wax Lake Delta, Cabo de Gata, the Siberian Traps: Geology covers the world
New Geology articles posted online ahead of print 22 Nov. 2013
Boulder, Colo., USA – Locations studied for this month's posting of Geology articles include New Zealand's ...
Golden staph paralyzes our immune defenses
2013-11-25
Golden staph paralyzes our immune defenses
A ringside seat in the war against infection
When golden staph enters our skin it can identify the key immune cells and 'nuke' our body's immune response.
Now we know how, thanks to an international research ...
Chinese scientists reveal the genomic enigma of desert poplar
2013-11-25
Chinese scientists reveal the genomic enigma of desert poplar
November 25, 2013, Shenzhen, China - In a collaborative study, researchers from Lanzhou University, BGI and other institutes have succeeded in unraveling the whole genome sequence of desert poplar, Populus euphratica, and the genetic ...
Ultra-sensitive force sensing with a levitating nanoparticle
2013-11-25
Ultra-sensitive force sensing with a levitating nanoparticle
ICFO scientists have optically levitated nanoparticles in high vacuum conditions and measured the highest Q-factor ever observed in nano- or micromechanical systems
A recent study ...
2 new beautiful wasp species of the rare genus Abernessia
2013-11-25
2 new beautiful wasp species of the rare genus Abernessia
Two new beautiful wasp species are added to the rare pompilid genus Abernessia, which now contains a total of only four known species. The two new species A. prima and A. capixaba are believed to be endemic for Brazil ...
Tidy knots are faster
2013-11-25
Tidy knots are faster
How long does it take a virus to infect a cell?
Viruses are as simple as they are "smart": too elementary to be able to reproduce by themselves, they exploit the reproductive "machinery" of cells, ...
Underestimated future climate change?
2013-11-25
Underestimated future climate change?
This news release is available in German. Many scientists believe that global warming will come to an end if, some day, human succeeds in stopping the release of greenhouse gas emissions into the atmosphere. It would, ...
LAST 30 PRESS RELEASES:
UMaine research examines best methods for growing Atlantic sea scallops
Medical cannabis could speed recovery, especially at community recovery homes
Study assesses U.S. image amid weakening of democracy
Two scientific researchers to receive 2025 Ralph L. Sacco Scholarships for Brain Health
Researchers improve chemical reaction that underpins products from foods to fuels
Texas Tech to develop semiconductor power devices through $6 million grant
Novel genomic screening tool enables precision reverse-engineering of genetic programming in cells
Hot Schrödinger cat states created
How cells repair their power plants
Oxygen is running low in inland waters—and humans are to blame
ACP’s Best Practice Advice addresses use of cannabis, cannabinoids for chronic noncancer pain
Beyond photorespiration: A systematic approach to unlocking enhanced plant productivity
How a small number of mutations can fuel outbreaks of western equine encephalitis virus
Exposure to wildfire smoke linked with worsening mental health conditions
Research uncovers hidden spread of one of the most common hospital-associated infections
Many older adults send their doctors portal messages, but who pays?
Fine particulate matter from 2020 California wildfires and mental health–related emergency department visits
Gender inequity in institutional leadership roles in US academic medical centers
Pancreatic cells ‘remember’ epigenetic precancerous marks without genetic sequence mutations
Rare combination of ovarian tumors found in one patient
AI-driven clinical recommendations may aid physician decision making to improve quality of care
Artificial intelligence has potential to aid physician decisions during virtual urgent care
ACP and Annals of Internal Medicine present breaking scientific news at ACP’s Internal Medicine Meeting 2025
New study reveals polymers with flawed fillers boost heat transfer in plastics
Signs identified that precede sudden arrhythmic death syndrome in young people
Discovery of bacteria's defence against viruses becomes a piece of the puzzle against resistance
Pre-eclampsia is associated with earlier onset and higher incidence of cardiovascular risk factors
Warwick astronomers discover doomed pair of spiralling stars on our cosmic doorstep
Soil conditions significantly increase rainfall in world’s megastorm hotspots
NK cells complexed with bispecific antibody yield high response rates in patients with lymphoma
[Press-News.org] Breaking the brain clock predisposes nerve cells to neurodegenerationFindings point to possible ways to fight some age-related diseases