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Discovery of agile molecular motors could aid in treating motor neuron diseases
July 18, 2006(Philadelphia, PA)-Over the last several months, the labs of Yale Goldman, MD, PhD, Director of the Pennsylvania Muscle Institute at the University of Pennsylvania School of Medicine, and Erika Holzbaur, PhD, Professor of Physiology, have published a group of papers that, taken together, show proteins that function as molecular motors are surprisingly flexible and agile, able to navigate obstacles within the cell. These observations could lead to better ways to treat motor neuron diseases.
Motor neuron diseases are a group of progressive neurological disorders that destroy motor neurons, the cells that control voluntary muscles for such activities as speaking, walking, breathing, and swallowing. When these neurons die, the muscle itself atrophies. A well-known motor neuron disease is amyotrophic lateral sclerosis (ALS, commonly known as Lou Gehrig's disease).
Using a specially-constructed microscope that allows researchers to observe the action of one macromolecule at a time, the team found that a protein motor is able to move back and forth along a microtubule - a molecular track - rather than in one direction, as previously thought. They report their findings in a recent issue of Nature Cell Biology. The proteins in this motor, dynein and dynactin, are the "long-distance truckers" of the cell: working together, they are responsible for transporting cellular cargo from the periphery of a cell toward its nucleus.
"My lab concentrates on the cellular and genetic aspects of the dynein-dynactin motor, while Yale's group delves into the mechanics of the motor itself," says Holzbaur. "We're deconstructing the system to understand how it all works in a living cell. In the lab, we start with a clean microtubule with a motor walking across it, but in the cell it's different: microtubules are packed together, with proteins studded along them, and cellular organelles and mitochondria are crammed in. The motor needs to maneuver around those 'obstructions.'" Goldman and Holzbaur suggest that the ability of the dynein-dynactin motor to move in both directions along the microtubule may provide the necessary maneuvering ability to allow for effective long distance transport.
Earlier this year, as reported in The Journal of Cell Biology, researchers in Holzbaur's lab found that a mutation in dynactin leads to degeneration of motor neurons, the hallmark of motor neuron disease. This mutation decreases the efficiency of the dynein-dynactin motor in "taking out the trash" of the cell, and thus leads to the accumulation of misfolded proteins in the cell, which may in turn lead to the degeneration of the neuron.
Scientists are now finding that many other molecular motors are remarkably flexible in their behavior. In several further papers published in the Proceedings of the National Academy of Sciences and The EMBO Journal, Goldman and colleagues at the University of Illinois found that a "local delivery" motor, termed myosin V, moves cargo with a variable path short distances along another type of cellular track called actin. This flexibility could help myosin V navigate crowded regions of the cell where the actin filaments criss-cross and where other cellular components would otherwise pose an impediment to motion. Defects in myosin V function also result in neurological defects.
Most of these molecular motors are associated with specific diseases or developmental defects, so understanding the puzzling aspects of their behavior in detail is necessary for building nanotechnological machines that, for example, could replace defective motors. "The ultimate goal is to find ways to treat motor neuron disease as well as other diseases that involve cellular motors and also construct nano-scale machines based on these biological motors," says Goldman.
University of Pennsylvania School of Medicine
"My lab concentrates on the cellular and genetic aspects of the dynein-dynactin motor, while Yale's group delves into the mechanics of the motor itself," says Holzbaur. "We're deconstructing the system to understand how it all works in a living cell. In the lab, we start with a clean microtubule with a motor walking across it, but in the cell it's different: microtubules are packed together, with proteins studded along them, and cellular organelles and mitochondria are crammed in. The motor needs to maneuver around those 'obstructions.'" Goldman and Holzbaur suggest that the ability of the dynein-dynactin motor to move in both directions along the microtubule may provide the necessary maneuvering ability to allow for effective long distance transport.
Earlier this year, as reported in The Journal of Cell Biology, researchers in Holzbaur's lab found that a mutation in dynactin leads to degeneration of motor neurons, the hallmark of motor neuron disease. This mutation decreases the efficiency of the dynein-dynactin motor in "taking out the trash" of the cell, and thus leads to the accumulation of misfolded proteins in the cell, which may in turn lead to the degeneration of the neuron.
Scientists are now finding that many other molecular motors are remarkably flexible in their behavior. In several further papers published in the Proceedings of the National Academy of Sciences and The EMBO Journal, Goldman and colleagues at the University of Illinois found that a "local delivery" motor, termed myosin V, moves cargo with a variable path short distances along another type of cellular track called actin. This flexibility could help myosin V navigate crowded regions of the cell where the actin filaments criss-cross and where other cellular components would otherwise pose an impediment to motion. Defects in myosin V function also result in neurological defects.
Most of these molecular motors are associated with specific diseases or developmental defects, so understanding the puzzling aspects of their behavior in detail is necessary for building nanotechnological machines that, for example, could replace defective motors. "The ultimate goal is to find ways to treat motor neuron disease as well as other diseases that involve cellular motors and also construct nano-scale machines based on these biological motors," says Goldman.
University of Pennsylvania School of Medicine
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Waging a War against Motor Neuron Disease: On the Frontier of Translational Research for Lou Gehrig's Disease by Page Jones (Author) Despite the great strides that have been made in research for Lou Gehrig?s Disease in the twentieth century, effective treatments are sorely lacking. This is a devastating neurodegenerative disorder that progresses rapidly to paralysis and death. What will we do to address treatment options? Waging a War against Motor Neuron Disease describes the development of a cell model and biochemical assays that may lead to the discovery of mechanisms of ALS. This original work provides groundbreaking evidence that proteomics analysis in spinal cord extracts of ALS mice may yield new protein targets and suggests that therapeutic approaches can be derived from developments in the laboratory. This book describes translational research that is leading to promising... |
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Motor Neuron Disease by Kunel (Author), Rutherford (Author), John L.R. Forsythe (Author), Ralph W. Kuncl MD PhD (Editor) Motor Neuron Disease is a state of the art monograph designed for the clinician who wants to stay on the cutting edge of the scientific understanding of motor neuron disease. The three most common motor neuron diseases are covered, namely sporadic amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis and childhood spinal muscular atrophy. Succinct, well referenced and supported by appropriate illustrations the scope of the book includes current accepted diagnostic criteria for ALS, including practical case histories to aid differential diagnosis. The most common theories of pathogenesis are examined, and the most up to date review of the genetic implications for familial ALS included. A chapter on treatment includes coverage of the latest anti-excitotoxic drugs, in... |
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Motor Neuron Disease (The Facts) by Kevin Talbot (Author), Rachael Marsden (Author) Motor neuron disease (MND) is a common but devastating disability that has a profound impact on people's lives. This book provides an easily-accessible guide to the disease for patients with motor neuron disease and their carers. The authors have organised it around a series of the commonest questions asked in their clinic, emphasising the variation in the course of MND and the individual nature of the patient journey through the disease. After an initial description of the symptoms for MND and how neurologists make the diagnosis the authors describe what is known about the causes and how scientists are trying to understand the disease. The book also looks at how a team of specialists can provide support and symptom control for the patient. |
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Motor neuron diseases: An entry from Thomson Gale's Gale Encyclopedia of Neurological Disorders by Brook, PhD Hall (Author) Targeted to patients, their families and allied health students, The “Gale Encyclopedia of Neurological Disorders” provides in-depth coverage of neurological diseases and disorders, including stroke, multiple sclerosis, Parkinson disease, Tourette Syndrome, Alzheimer's disease, cerebral palsy, vertigo, amnesia and epilepsy. Related topics include communication aids, electric personal assistive mobility devices, medications for treating neurological diseases and conditions, understanding the needs of Alzheimer patient caregivers and more. This two-volume set provides an alternative to resources that either fail to explore neurological disease in any depth and or do so at a level not appropriate for students and general readers. | |
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Motor Neuron Disease by A. C. Williams (Editor) Motor neurone disease (amyotrophic lateral sclerosis) is one of several neurological diseases of unknown cause. It is an illness that rarely runs in families, nor do epidemics occur. It is therefore likely to be due to a multifactorial process, probably with a genetically determined susceptibility to some environmental insult. Provided in this book is a comprehensive and up-to-date text on motor neurone disease. It covers many aspects of the disease, including clinical descriptions and discussions on management of both early and late cases. Personal views of a carer are also included as well as the aetiology and molecular basis of this disease. | |
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Human Motor Neuron Diseases (Advances in Neurology) by Rowland (Author), Lewis P. Rowland (Other Contributor) | |
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Clinical Electromyography. A Brief Review of the Electrophysiology of the Motor Unit and Its Application to the Diagnosis of Lower Motor Neuron Diseases, Peripheral Neuropathy and the Myopathies. by Alberto A. MARINACCI (Author) |
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