 |
|
Salk and Stanford teams join forces to reveal two paths of neurodegeneration
June 15, 2006LA JOLLA, CA—Wiring the developing brain is like creating a topiary garden. Shrubs don't automatically assume the shape of ornamental elephants, and neither do immature nerve cells immediately recognize the "right" target cell. Abundant foliage, either vegetal or neuronal, must first sprout and then be sculpted into an ordered structure.
Neurons extend fibers called axons to target cells in an exuberant manner—some branch to the "wrong" cells while others shoot past their target cells. Axon pieces that went astray degenerate, effectively being "pruned" back. Similarly, when axons are forcibly severed or seriously injured by disease in adults, they die and are removed by degeneration.
Scientists have speculated that the same molecular shears used to trim axon branches in injured adult axons also do so during normal developmental pruning. In a forthcoming issue of Neuron, teams at the Salk Institute for Biological Studies and Stanford University revise that notion and, in doing so, suggest how nerve function could be preserved after injury.
The collaboration began when senior co-authors Liqun Luo, PhD., a professor at Stanford University and Howard Hughes Medical Investigator, and Dennis D.M. O'Leary, a professor in the Salk Molecular Neurobiology Laboratory, co-wrote a review on neurodegeneration. Of O'Leary, Luo says, "When they asked me to write this review I found that half these things were started by Dennis." O'Leary adds, "We had a great time writing the review and it hatched the idea to combine our ideas."
They combined data collected by Luo's lab in fruitflies with experiments done in mice by O'Leary and co-lead author Todd McLaughlin, a postdoctoral fellow in the O'Leary lab.
When cut, axons in mice or fruitflies degenerate quickly. However, in so called Wlds mice, a naturally occurring mutant strain discovered years ago, the process is slowed, because the mice make a mutant protein—known as Wlds —that inhibits degeneration.
But the mutant Wlds protein doesn't hamper the wiring process in developing brains. In newborn Wlds mice, axons extending from nerve cells (called RGCs) in the retina to a brain center called the superior colliculus were still undergoing their normal pruning process, the Salk researchers observed,
These findings show that axon degeneration after injury or developmental pruning requires different activities. "Superficially they look the same," says O'Leary, "but our studies show that they are mechanistically different, at least at the initial stages."
Thinking this could be age-related, McLaughlin cut the same axons in newborn Wlds mice and found that degeneration was slowed. "When I saw RGC axons in the superior colliculus that appeared morphologically perfect five days after they had been completely separated from RGCs, I was thrilled," says McLaughlin.
Meanwhile at Stanford, Luo's graduate student and co-lead author Eric Hoopfer together with McLaughlin, made "transgenic" fruitflies carrying the Wlds gene and found it had no effect on axon pruning during development, but that it did slow degeneration in cut axons — just like in mice.
Hoopfer explains that an early hypothesis was that "the axon degeneration at the heart of neurodegenerative diseases may be a misuse of normal pruning programs, but our studies suggest that two different mechanisms are involved."
According to Luo, these findings also suggest strategies to slow neurodegeneration. "Wlds protein protects axons after injury and has been shown to be effective in delaying degeneration not just after injury, but in diseases similar to Parkinson's disease or motor neuron injury," he explains.
Luo and O'Leary believe that the conservation of the differences in axon degeneration between developmental pruning and injury from flies to mammals points to general mechanisms which are most likely also at work in the human nervous system. Both investigators believe that these and related studies can help in the development of therapies that preserve injured axons and restore proper connections.
Other researchers who contributed to this paper included postdoctoral fellow Oren Schuldiner, Ph.D., at Stanford and Ryan Watts, Ph.D., formerly a Ph.D. student in Luo's lab and now a scientist at Genentech.
Salk Institute
The collaboration began when senior co-authors Liqun Luo, PhD., a professor at Stanford University and Howard Hughes Medical Investigator, and Dennis D.M. O'Leary, a professor in the Salk Molecular Neurobiology Laboratory, co-wrote a review on neurodegeneration. Of O'Leary, Luo says, "When they asked me to write this review I found that half these things were started by Dennis." O'Leary adds, "We had a great time writing the review and it hatched the idea to combine our ideas."
They combined data collected by Luo's lab in fruitflies with experiments done in mice by O'Leary and co-lead author Todd McLaughlin, a postdoctoral fellow in the O'Leary lab.
When cut, axons in mice or fruitflies degenerate quickly. However, in so called Wlds mice, a naturally occurring mutant strain discovered years ago, the process is slowed, because the mice make a mutant protein—known as Wlds —that inhibits degeneration.
But the mutant Wlds protein doesn't hamper the wiring process in developing brains. In newborn Wlds mice, axons extending from nerve cells (called RGCs) in the retina to a brain center called the superior colliculus were still undergoing their normal pruning process, the Salk researchers observed,
These findings show that axon degeneration after injury or developmental pruning requires different activities. "Superficially they look the same," says O'Leary, "but our studies show that they are mechanistically different, at least at the initial stages."
Thinking this could be age-related, McLaughlin cut the same axons in newborn Wlds mice and found that degeneration was slowed. "When I saw RGC axons in the superior colliculus that appeared morphologically perfect five days after they had been completely separated from RGCs, I was thrilled," says McLaughlin.
Meanwhile at Stanford, Luo's graduate student and co-lead author Eric Hoopfer together with McLaughlin, made "transgenic" fruitflies carrying the Wlds gene and found it had no effect on axon pruning during development, but that it did slow degeneration in cut axons — just like in mice.
Hoopfer explains that an early hypothesis was that "the axon degeneration at the heart of neurodegenerative diseases may be a misuse of normal pruning programs, but our studies suggest that two different mechanisms are involved."
According to Luo, these findings also suggest strategies to slow neurodegeneration. "Wlds protein protects axons after injury and has been shown to be effective in delaying degeneration not just after injury, but in diseases similar to Parkinson's disease or motor neuron injury," he explains.
Luo and O'Leary believe that the conservation of the differences in axon degeneration between developmental pruning and injury from flies to mammals points to general mechanisms which are most likely also at work in the human nervous system. Both investigators believe that these and related studies can help in the development of therapies that preserve injured axons and restore proper connections.
Other researchers who contributed to this paper included postdoctoral fellow Oren Schuldiner, Ph.D., at Stanford and Ryan Watts, Ph.D., formerly a Ph.D. student in Luo's lab and now a scientist at Genentech.
Salk Institute
Neurodegeneration Current Events and Neurodegeneration News RSSSchizophrenia gene's role may be broader, more potent, than thought
UCSF scientists studying nerve cells in fruit flies have uncovered a new function for a gene whose human equivalent may play a critical role in schizophrenia.
Research reveals lipids' unexpected role in triggering death of brain cells
The lipid that accumulates in brain cells of individuals with an inherited enzyme disorder also drives the cell death that is a hallmark of the disease, according to new research led by St. Jude Children's Research Hospital investigators.
Statins show dramatic drug and cell dependent effects in the brain
Besides their tremendous value in treating high cholesterol and lowering the risk of heart disease, statins have also been reported to potentially lower the risks of other diseases, such as dementia.
Trembling hands and molecular handshakes
Fragile X tremor/ataxia syndrome (FXTAS) is a recently recognized condition, which is actually one of the most prevalent heritable neurodegenerative diseases.
Alzheimer's researchers find high protein diet shrinks brain
One of the many reasons to pick a low-calorie, low-fat diet rich in vegetables, fruits, and fish is that a host of epidemiological studies have suggested that such a diet may delay the onset or slow the progression of Alzheimer's disease (AD).
Study examines treatment for olfactory loss after viral infection
Treatment with a glucocorticoid medication, either alone or in combination with Ginkgo biloba, appears to significantly improve the sense of smell in individuals with previous olfactory loss due to upper respiratory infections.
How Proteins Talk to Each Other
Investigators at Burnham Institute for Medical Research (Burnham) have identified novel cleavage sites for the enzyme caspase-3 (an enzyme that proteolytically cleaves target proteins).
Reactive Oxygen's Role in Metastasis
Researchers at the Burnham Institute for Medical Research (Burnham) have discovered that reactive oxygen species, such as superoxide and hydrogen peroxide, play a key role in forming invadopodia, cellular protrusions implicated in cancer cell migration and tumor metastasis.
New Insights Into Cardiac Aging
Investigators at Burnham Institute for Medical Research (Burnham) have found that the conserved protein d4eBP modulates cardiac aging in Drosophila (fruit flies).
When Proteins Change Partners
Dieter Wolf, M.D., and colleagues at Burnham Institute for Medical Research (Burnham) have illuminated how competition between proteins enhances combinatorial diversity during ubiquitination (the process that marks proteins for destruction).
More Neurodegeneration Current Events and Neurodegeneration News Articles
 |
The Proteasome in Neurodegeneration by Leonidas Stefanis (Editor), J.N. Keller (Editor) There is increasing evidence that links together various common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. Finding common themes in the pathophysiology of such disorders is increasingly important. This text addresses such a common theme—the proteasome. Since the discovery of the proteasome some 20 years ago, significant strides have been made in our understanding of proteasome biology and our understanding of the role the proteasome plays in a wide variety of biochemical events. Taken together, these studies have confirmed an important role for the proteasome in the fields of cell biology, oncology, immunology, gerontology, and neuroscience. The focus of this book is to provide an in depth analysis and provocative discussion of what... |
 |
Advances in Research on Neurodegeneration: Volume 10 (Advances in Research on Neurodegeneration, 10) by R. Horowski (Editor), Y. Mizuno (Editor), C.W. Olanow (Editor), W. Poewe (Editor), P. Riederer (Editor), J.A. Stoessel (Editor), M.B.H. Youdim (Editor) Neurobiotec, Berlin, Germany. Presents the proceedings from the 10th International Winter Conference on Neurodegeneration, held in Berlin, Germany, February 14-16, 2002. |
 |
Metal-based Neurodegeneration: From Molecular Mechanisms to Therapeutic Strategies by Robert Crichton (Author), Roberta Ward (Author) This exciting new book opens a window into the causes of debilitating neurological disorders such as Parkinson’s disease, CJD and Huntington’s disease, and gives indications of the prospects for therapy, based on the understanding of molecular defects involved in these diseases. Looking at each specific neurological disorder in turn, the book outlines the role of metals in human biology, in particular in the brain and explores tools for testing potential therapeutic strategies. It concludes with an overview of the potential of both chelation and antioxidant therapy and outlines some perspectives for the future. |
 |
Neurodegeneration Methods and Protocols (Methods in Molecular Medicine) by Jean Harry (Editor), Hugh A. Tilson (Editor) Techniques for studying many aspects of nervous system cell biology. Contains notes about potential pitfalls and tips on how to avoid failures. Modified-outline format. DNLM: Nerve Degeneration. |
 |
Neurodegeneration and Prion Disease by David R. Brown (Editor) This volume provides an in-depth overview from world experts on prion disease. These fatal diseases include Creutzfeldt-Jakob disease, chronic wasting disease in deer, scrapie of sheep, bovine spongiform encephalopathy (mad cow’s disease) of cattle and related diseases. Understanding what causes neuronal death in these diseases is essential to both preventing and curing them. The most recent advances in understanding neuronal death in prion diseases are presented. Prion diseases serve as an experimental model for all neurodegenerative conditions. This book will provide understanding of neurodegeneration and provide an up-to-date record of the state of the art for other specialists and non-specialists in related fields. |
 |
New Perspectives on Brain Cell Damage, Neurodegeneration and Neuroprotective Strategies 2007 by Editor-in-Chief: Abel Santamaria (Author), Associate Editor: Maria Esther Jimenez-Capdeville (Author), Editor-in-Chief: Abel Santamaria (Editor) From the Preface For the last four decades, the study of the functioning and pathological alterations of the Nervous System has been intensified in search for therapeutic alternatives against neurodegenerative disorders in humans. Since their first descriptions in the 19th and 20th centuries, sufficient clinical and experimental findings contributed to describe the origin of some of the most common and frequent neurological diseases. Derived from this multidisciplinary research performed along decades, now we know that a great number of factors trigger nerve tissue damage and cell death, and they include the environmental exposure to toxicants, inheritance patterns, the individual susceptibility to endogenous or exogenous neurotoxins, ageing processes, traumatic injury, drug... |
 |
Progress in Neurodegeneration: The Role of Metals (Neurodegenerative Diseases-Laboratory and Clinical Research Series) by Maria Rosa Avila-Costa (Editor), Veronica Anaya Martinez (Editor) This book highlights the role of some metals which induce oxidative stress and imbalances in the neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Amyotrophic Lateral Sclerosis, Huntington Disease, and other dementias. The chemistry and biochemistry of metals induced-oxidative stress, protein damage is first described, followed by the evidence for a pathological role of oxidative stress in these disease states. It is tempting to speculate that free radical oxygen chemistry contributes to pathogenesis in all these conditions, though it is as yet undetermined what types of oxidative changes occur early in the disease, and what types are secondary manifestations of neuronal degeneration. Finally the authors review different metals to describe their specific role in the... |
 |
Nrf2 as a Therapeutic Target for Stroke and Neurodegeneration by Andy Yi-an Shih (Author) Stroke is a leading cause of death and disability in North America. One major cause of nerve tissue damage during stroke is the accumulation of reactive oxygen species- molecules that steal electrons from healthy cells in a process known as oxidation. This thesis describes a novel approach to increase antioxidant levels in order to maintain oxidative balance and prevent cellular damage during stroke. The stress-responsive transcription factor, Nrf2, is able to launch the endogenous mechanisms of cellular defense and repair. Nrf2 represents a master switch that coordinates tens to hundreds of antioxidant and detoxification genes working in synergy. In rodent models of stroke and neurodegeneration, increased Nrf2 activity was found to promote neuronal ... |
 |
Neurodegeneration in Multiple Sclerosis (Topics in Neuroscience) by M. Filippi (Editor), M. Rovaris (Editor), G. Comi (Editor) In multiple sclerosis (MS), conventional magnetic resonance imaging (cMRI) has proved to be a valuable tool to increase diagnostic confidence and for monitoring the efficacy of experimental treatment. However, cMRI has limited specificity and accuracy of cMRI to the most disabling aspects of the MS pathology, known to occur in and outside macroscopic lesions. Modern quantitative MR techniques have the potential to overcome the limitations of cMRI, and their application is changing dramatically our understanding of how MS causes irreversible disability. In detail, there is an increasing body of MR evidence that MS is not only a white matter disease and does not only cause focal lesions, as well as that neurodegeneration is an important aspect of the disease (since the earliest clinical... |
|
Power Cracking of Cash Cord Codes / Flies Carry Gene for Alcohol Sensitivity / Unveiling the Tau of Neurodegeneration / Protein's Shape May Give Extra-Sugary Taste / Computer Model Captures Missing Matter / Healthy Functioning Takes Social Cues (Science News, Volume 153, Number 25, June 20, 1998) by Julie Ann Miller (Editor) |
| © 2009 BrightSurf.com |