Switching off a key DNA repair system in the developing nervous system is linked to smaller brain size as well as problems in brain structures vital to movement, memory and emotion, according to new research led by St. Jude Children's Research Hospital scientists.
The work, published in the August issue of the journal Nature Neuroscience, also provides the first evidence that cells known as cerebellar interneurons are targeted for DNA damage and are a likely source of neurological problems in humans. The cerebellum coordinates movement and balance. The cerebellar interneurons fine tune motor control.
"These data will be important for understanding the role the DNA damage response plays in preventing neurological disease," the investigators wrote.
The study also marks the first time researchers have switched off a pathway for repairing damaged single DNA strands in an organ system, in this case the mouse brain and nervous system. While the results suggest certain brain cells are particularly vulnerable, investigators report that with time DNA damage accumulates throughout the nervous system. Some mice in the study eventually develop seizures and difficulty walking.
Peter J. McKinnon, Ph.D., a member of St. Jude Genetics and Tumor Cell Biology, said the work provides a new model for understanding how single-strand DNA damage affects the nervous system and offers a new focus for tracking the origins of neurological disease.
The research also reflects growing scientific interest in damage to single strands of DNA. "A variety of human disease syndromes result from problems in the DNA-repair system," explained McKinnon, the paper's senior author.
DNA is the double-stranded molecule found in nearly every cell. In organisms both simple and complex, it serves as the biochemical blueprint for assembling and sustaining life. Diseases like cancer have long been associated with unrepaired damage to both strands of DNA. Single-strand DNA damage is far more common, but was generally considered less catastrophic to the cell.
But the last decade brought evidence linking single-strand DNA damage with human diseases, including ataxia with oculomotor apraxia (AOA1) and spinocerebellar ataxia with axonal neuropathy (SCAN1). Both disorders are inherited and are characterized by progressive difficulty with walking and other movement. AOA1 is among the most common form of certain inherited movement disorders in Japan and Portugal. McKinnon said those reports sparked new interest in single-strand DNA repair.
This study focused on Xrcc1, a protein long recognized as the master regulator of a pathway essential for single-strand DNA repair in the nervous system. The brain is thought to be particularly susceptible to such damage because neurons consume large amounts of oxygen, which can result in excessive production of free radicals and leave them vulnerable to single-strand DNA damage. Because brain cells do not divide, they cannot use the backup repair systems found in other tissues.
Investigators developed a way to switch off Xrcc1 production in the mouse brain and nervous system as development began. The system meant Xrcc1 still worked normally in the rest of the body.
The strategy used mice developed to make a particular enzyme, known as cre recombinase, in just the nervous system. St. Jude researchers then developed a mouse that carried an Xrcc1 gene outfitted with biochemical tags targeting the gene for inactivation by the enzyme. The result was a mouse whose nervous system lacked Xrcc1 and so was unable to efficiently repair the single-strand DNA damage.
The shutdown triggered a dramatic decline of interneurons throughout the cerebellum. In a subgroup of those cells, the damage triggered apoptosis, or programmed cell death. But the findings suggested the greatest loss occurred as the immature cerebellar interneurons, or progenitor cells, were poised to complete differentiation. In those cells, McKinnon said, loss of Xrcc1 activated the p53 pathway and blocked the cells from completing the cell cycle. "The cells appear to undergo permanent arrest," said McKinnon, noting it is one of the few in vivo examples of the p53 pathway leading to cell cycle arrest rather than apoptosis.
In the hippocampus, which plays a role in memory and emotion, investigators reported abnormal gene expression and neuronal function. Some neurons were eventually replaced by scar tissue in a process known as gliosis. Overall changes in the hippocampus mimicked those found in the brains of adults with the seizure disorder known as temporal lobe epilepsy. In this study, the loss of Xrcc1 also resulted in seizures in mice.
The other authors of this paper were Youngsoo Lee, Sachin Katyal, Yang Li and Helen R. Russell, all of St. Jude; and Sherif F. El-Khamisy and Keith W. Caldecott of the University of Sussex, Brighton, UK.
The work was supported in part by the National Institutes of Health and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.
Summer Freeman | EurekAlert!
Rochester scientists discover gene controlling genetic recombination rates
23.04.2018 | University of Rochester
One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
23.04.2018 | Earth Sciences
23.04.2018 | Trade Fair News
23.04.2018 | Information Technology