Posts tagged science

(Source: sfu.ca)

St. Jude Children’s Research Hospital scientists studying two rare, inherited childhood neurodegenerative disorders have identified a new, possibly common source of DNA damage that may play a role in other neurodegenerative diseases, cancer and aging. The findings appear in the current issue of the scientific journal Nature Neuroscience.

Researchers showed for the first time that an enzyme required for normal DNA functioning causes DNA damage in the developing brain. DNA is the molecule found in nearly every cell that carries the instructions needed to assemble and sustain life.

The enzyme is topoisomerase 1 (Top1). Normally, Top1 works by temporarily attaching to and forming a short-lived molecule called a Top1 cleavage complex (Top1cc). Top1ccs cause reversible breaks in one strand of the double-stranded DNA molecule. That prompts DNA to partially unwind, allowing cells to access the DNA molecule in preparation for cell division or to begin production of the proteins that do the work of cells.

Different factors, including the free radicals that are a byproduct of oxygen metabolism, result in Top1ccs becoming trapped on DNA and accumulating in cells. This study, however, is the first to link the buildup to disease. The results also broaden scientific understanding of the mechanisms that maintain brain health.

Investigators made the connection between DNA damage and accumulation of Top1cc while studying DNA repair problems in the rare neurodegenerative disorders ataxia telangiectasia (A-T) and spinocerebellar ataxia with axonal neuropathy 1(SCAN1). The diseases both involve progressive difficulty with walking and other movement. This study showed that A-T and SCAN1 also share the buildup of Top1ccs as a common mechanism of DNA damage. A-T is associated with a range of other health problems, including an increased risk of leukemia, lymphoma and other cancers.

“We are now working to understand how this newly recognized source of DNA damage might contribute to tumor development or the age-related DNA damage in the brain that is associated with neurodegenerative disorders like Alzheimer’s disease,”said co-corresponding author Peter McKinnon, Ph.D., a member of the St. Jude Department of Genetics. The co-corresponding author is Sachin Katyal, Ph.D., of the University of Manitoba Department of Pharmacology and Therapeutics and formerly of St. Jude.

A-T and SCAN1 are caused by mutations in different enzymes involved in DNA repair. Mutations in the ATM protein lead to A-T. Alterations in the Tdp1 protein cause SCAN1.

Working in nerve cells growing in the laboratory and in the nervous system of specially bred mice, researchers showed for the first time that ATM and Tdp1 work cooperatively to repair breaks in DNA. Scientists also demonstrated how the proteins accomplish the task.

The results revealed a new role for ATM in repairing single-strand DNA breaks. Until this study, ATM was linked to double-strand DNA repair. ATM was also known to work exclusively as a protein kinase. Kinases are enzymes that use chemicals called phosphate groups to regulate other proteins.

Scientists reported that when Top1ccs are trapped ATM functions as a protein kinase and alert cells to the DNA damage. But researchers found ATM also serves a more direct role by marking the trapped Top1ccs for degradation by the protein complex cells use to get rid of damaged or unnecessary proteins. ATM accomplishes that task by promoting the addition of certain proteins called ubiquitin and SUMO to the Top1cc surface.

Tdp1 then completes the DNA-repair process by severing the chemical bonds that tether Top1 to DNA.

Mice lacking either Atm or Tdp1 survived with apparently normal neurological function. But compared to normal mice, the animals missing either protein had elevated levels of Top1cc. Those levels rose sharply during periods of rapid brain development and in response to radiation, oxidation and other factors known to cause breaks in DNA.

When researchers knocked out both Atm and Tdp1, Top1cc accumulation rose substantially as did a form of programmed cell death called apoptosis. Investigators reported that apoptosis was concentrated in the developing brain and few mice survived to birth. McKinnon said the results add to evidence that the brain is particularly sensitive to DNA damage.

Researchers then used the anti-cancer drug topotecan to link elevated levels of Top1cc to the cell death and other problems seen in mice lacking Atm and Tdp1. Topotecan works by trapping Top1ccs in tumor cells, resulting in the DNA damage that triggers apoptosis. Investigators showed that the impact of Top1cc accumulation was strikingly similar whether the cause was topotecan or the loss of Atm and Tdp1.

(Source: stjude.org)

In a paper published in the latest issue of the neuroscience journal Neuron, McLean Hospital investigators report that a gene essential for normal brain development, and previously linked to Autism Spectrum Disorders, also plays a critical role in addiction-related behaviors.

"In our lab, we investigate the brain mechanisms behind drug addiction – a common and devastating disease with limited treatment options," explained Christopher Cowan, PhD, director of the Integrated Neurobiology Laboratory at McLean and an associate professor of Psychiatry at Harvard Medical School. "Chronic exposure to drugs of abuse causes changes in the brain that could underlie the transition from casual drug use to addiction. By discovering the brain molecules that control the development of drug addiction, we hope to identify new treatment approaches."

The Cowan lab team, led by Laura Smith, PhD, an instructor of Psychiatry at Harvard Medical School, used animal models to show that the fragile X mental retardation protein, or FMRP, plays a critical role in the development of addiction-related behaviors. FMRP is also the protein that is missing in Fragile X Syndrome, the leading single-gene cause of autism and intellectual disability. Consistent with its important role in brain function, the team found that cocaine utilizes FMRP to facilitate brain changes involved in addiction-related behaviors.

Cowan, whose work tends to focus on identifying novel genes related to conditions such as autism and drug addiction, explained that FMRP controls the remodeling and strength of connections in the brain during normal development. Their current findings reveal that FMRP plays a critical role in the changes in brain connections that occur following repeated cocaine exposure.

"We know that experiences are able to modify the brain in important ways. Some of these brain changes help us, by allowing us to learn and remember. Other changes are harmful, such as those that occur in individuals struggling with drug abuse," noted Cowan and Smith. "While FMRP allows individuals to learn and remember things in their environment properly, it also controls how the brain responds to cocaine and ends up strengthening drug behaviors. By better understanding FMRP’s role in this process, we may someday be able to suggest effective therapeutic options to prevent or reverse these changes."

(Source: eurekalert.org)

An estimated 15-20 percent of U.S. troops returning from Iraq and Afghanistan suffer from some form of traumatic brain injury (TBI) sustained during their deployment, with most injuries caused by blast waves from exploded military ordnance. The obvious cognitive symptoms of minor TBI — including learning and memory problems — can dissipate within just a few days. But blast-exposed veterans may continue to have problems performing simple auditory tasks that require them to focus attention on one sound source and ignore others, an ability known as “selective auditory attention.”

According to a new study by a team of Boston University (BU) neuroscientists, such apparent “hearing” problems actually may be caused by diffuse injury to the brain’s prefrontal lobe — work that will be described at the 167th meeting of the Acoustical Society of America, to be held May 5-9, 2014 in Providence, Rhode Island.

"This kind of injury can make it impossible to converse in everyday social settings, and thus is a truly devastating problem that can contribute to social isolation and depression," explains computational neuroscientist Scott Bressler, a graduate student in BU’s Auditory Neuroscience Laboratory, led by biomedical engineering professor Barbara Shinn-Cunningham.

For the study, Bressler, Shinn-Cunningham and their colleagues — in collaboration with traumatic brain injury and post-traumatic stress disorder expert Yelena Bogdanova of VA Healthcare Boston — presented a selective auditory attention task to 10 vets with mild TBI and to 17 control subjects without brain injuries. Notably, on average, veterans had hearing within a normal range.

In the task, three different melody streams, each comprised of two notes, were simultaneously presented to the subjects from three different perceived directions (this variation in directionality was achieved by differing the timing of the signals that reached the left and right ears). The subjects were then asked to identify the “shape” of the melodies (i.e., “going up,” “going down,” or “zig-zagging”) while their brain activity was measured by electrodes on the scalp.

"Whenever a new sound begins, the auditory cortex responds, encoding the sound onset," Bressler explains. "Attentional focus, however, changes the strength of this response: when a listener is attending to a particular sound source, the neural activity in response to that sound is greater." This change of the neural response occurs because the brain’s "executive control" regions, located in the brain’s prefrontal cortex, send signals to the auditory sensory regions of the brain, modulating their response.

The researchers found that blast-exposed veterans with TBI performed worse on the task — that is, they had difficulty controlling auditory attention — “and in all of the TBI veterans who performed well enough for us to measure their neural activity, 6 out of our 10 initial subjects, the brain response showed weak or no attention-related modulation of auditory responses,” Bressler says.

"Our hope is that some of our findings can be used to develop methods to assess and quantify TBI, identifying specific factors that contribute to difficulties communicating in everyday settings," he says. "By identifying these factors on an individual basis, we may be able to define rehabilitation approaches and coping strategies tailored to the individual."

Some TBI patients also go on to develop chronic traumatic encephalopathy (CTE) — a debilitating progressive degenerative disease with symptoms that include dementia, memory loss and depression — which can now only be definitively diagnosed after death. “With any luck,” Bressler adds, “neurobehavioral research like ours may help identify patients at risk of developing CTE long before their symptoms manifest.”

(Source: newswise.com)