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ScienceWeek
MEDICAL BIOLOGY: ANTIBIOTICS AND NEURODEGENERATIVE DISEASES
The following points are made by T.M. Miller and D.W. Cleveland (Science 2005 307:361):
1) It is difficult to overstate the impact of penicillin and the family of beta-lactam antibiotics since their introduction into clinical medicine in the early 1940s. These drugs act by inhibiting assembly of the protective outer wall of bacteria. Their impact on the treatment of a wide variety of infections has been nothing short of miraculous. But this family of wonder drugs from the last century may have yet more untapped therapeutic potential. New work[1] demonstrates that certain beta-lactam antibiotics have potential as neurotherapeutics for treating neurological diseases such as amyotrophic lateral sclerosis (ALS), adult motor neuron disease, and ischemic injury.
2) The evidence for this remarkable finding has arisen from a unique public-private partnership between the National Institute of Neurologic Disorders and Stroke of the NIH and a consortium of disease-oriented philanthropic organizations, including the ALS Association, the Huntington's Disease Society of America, and the Hereditary Disease Foundation. This consortium sponsored a drug screening effort that ignored the hundreds of thousands of compounds within the traditional chemical libraries mined by pharmaceutical companies. Instead, the consortium screened 1040 bioactive compounds, 750 of which were already approved by the FDA for use in humans. These compounds were then tested for their efficacy in multiple assays associated with one or more neurological diseases by 27 separate academic laboratories.
3) The first insight to emerge from this approach was a surprising new function for 15 beta-lactam antibiotics, including penicillin and a more modern variant, ceftriaxone, that enters the brain by crossing the blood-brain barrier. These antibiotics selectively induce transcription of the gene encoding the EAAT2 glutamate transporter; other classes of antibiotics do not have these effects. Glutamate is crucial for normal signal transmission between many types of neurons, including the motor neurons whose job is to trigger muscle contraction and whose premature death produces the progressive paralysis characteristic of ALS. Upper motor neurons extend processes from the brain into the spinal cord, where they form synaptic attachments directly with the lower motor neurons or indirectly through intermediate neurons. The axonal processes of the lower motor neurons extend out of the spinal cord and form connections with muscle.
4) These neurons communicate with each other by release from the presynaptic cell of the neurotransmitter glutamate, which then binds to receptors expressed by the lower motor neuron. Glutamate receptor activation triggers local membrane depolarization and generation of an electrical impulse that propagates down the full length of the neuron, where it stimulates release of another neurotransmitter that provokes contraction of the muscle. In the spinal cord, a non-neuronal supporting cell, the astrocyte, provides a key element in this signaling pathway -- that is, a rapid off switch for the glutamate signal. It does this by juxtaposing a fingerlike projection adjacent to the synapse between the two motor neurons. On the surface of this projection are EAAT2 glutamate transporters, which are glutamate pumps that allow efficient recovery of released glutamate and hence rapid silencing of the glutamate signal.
5) Excessive glutamate levels in the synapse and associated repetitive firing of neurons results in excitotoxic injury to neurons, a feature of many neurological disorders including stroke, spinal cord injury, and ALS [2]. Excitotoxicity is one of the best links between the rare familial form of ALS (caused by mutations in the gene encoding superoxide dismutase) and the more common sporadic form of this disease [3]. This realization came from studies in the early 1990s that showed increased glutamate in the fluid surrounding the brain and spinal cord of patients with sporadic ALS [4,5]. Similarly, in a rat model of familial ALS, animals develop focal loss of the EAAT2 glutamate transporter in regions of the spinal cord that house motor neurons. Indeed, the only approved medication for treating ALS, the drug riluzole, is thought to act by limiting synaptic glutamate release. The effectiveness of this drug, however, has been disappointing, extending survival of ALS patients by a mere 3 months.
References (abridged):
1. J. D. Rothstein et al., Nature 433, 73 (2005)
2. M. P. Mattson, Neuromol. Med. 3, 65 (2003)
3. P. R. Heath, P. J. Shaw, Muscle Nerve 26, 438 (2002)
4. J. D. Rothstein et al., Ann. Neurol. 28, 18 (1990)
5. J. D. Rothstein et al., Ann. Neurol. 30, 224 (1991)
Science http://www.sciencemag.org
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Related Material:
AXONAL SELF-DESTRUCTION AND NEURODEGENERATION
The following points are made by M.C. Raff et al (Science 2002 296:868):
1) Much effort is being devoted to understanding the nature of neuronal cell death in various neurodegenerative diseases such as motor neuron disease, glaucoma, and Alzheimer, Parkinson, and Huntington diseases (1-5). It may be, however, that neuronal death in these diseases occurs too late to be clinically important. Degeneration of the neuron's long process -- the axon -- often precedes the death of the cell body and may make a more important contribution to the patient's disability.
2) A classical example of axonal degeneration is "Wallerian degeneration", which occurs when an axon is cut. The part of the axon that is now disconnected from the cell body disassembles in a characteristic and orderly way. In vertebrates, this part of the axon can continue to conduct action potentials for a day or two when electrically stimulated, but it then quickly degenerates: The endoplasmic reticulum breaks down, the neurofilaments degrade, the mitochondria swell, and the axon breaks up into fragments that are phagocytosed. Wallerian degeneration can occur in both the peripheral nervous system (PNS) and central nervous system (CNS) whenever trauma, a vascular accident, infection, or an immune response locally injures axons.
3) From the perspective of neurodegenerative diseases, a more relevant form of axonal degeneration occurs in a process called "dying back". Here, the axon of an unhealthy neuron progressively degenerates over weeks or months, beginning distally and spreading toward the cell body. This is the most common pathology seen in peripheral nerve diseases caused by a wide variety of toxic, metabolic, and infectious insults. It occurs, for example, in the polyneuropathies associated with diabetes, alcoholism, acrylamide poisoning, and AIDS. It also seems to occur in CNS neurodegenerative diseases, including motor neuron disease and Alzheimer and Parkinson diseases, although it has been less well documented in these cases. The dying-back process is intriguing: How can a cell eliminate part of itself while leaving the rest intact? It contrasts with Wallerian degeneration, in which the axonal lesion itself both starts the destructive process and compartmentalizes it.
4) In summary: Neurons seem to have at least two self-destruct programs. Like other cell types, they have an intracellular death program for undergoing apoptosis when they are injured, infected, or not needed. In addition, they apparently have a second, molecularly distinct self-destruct program in their axon. This program is activated when the axon is severed and leads to the rapid degeneration of the isolated part of the cut axon. Do neurons also use this second program to prune their axonal tree during development and to conserve resources in response to chronic insults?
References (abridged):
1. C. Behl, J. Neural Transm. 107, 1325 (2000)
2. R. M. Gibson, Br. Med. J. 322, 1539 (2001)
3. N. Heintz and H. Y. Zoghbi, Annu. Rev. Physiol. 62, 779 (2000)
4. L. J. Martin, Int. J. Mol. Med. 7, 455 (2001)
5. N. N. Osborne, et al., Br. J. Ophthalmol. 83, 980 (1999)
Science http://www.sciencemag.org
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Related Material:
TOXIC PROTEINS IN NEURODEGENERATIVE DISEASE
The following points are made by J.P Taylor et al (Science 2002 296:1991):
1) Neurodegenerative disorders as diverse as Alzheimer's disease, Parkinson's disease, prion diseases, Huntington's disease, frontotemporal dementia, and motor neuron disease all share a conspicuous common feature -- aggregation and deposition of abnormal protein. Expression of mutant proteins in transgenic animal models recapitulates features of these diseases (1). Neurons are particularly vulnerable to the toxic effects of mutant or misfolded protein. The common characteristics of these neurodegenerative disorders suggest parallel approaches to treatment, based on an understanding of the normal cellular mechanisms for disposing of unwanted and potentially noxious proteins.
2) Correct folding requires proteins to assume one particular structure from a constellation of possible but incorrect conformations. The failure of polypeptides to adopt their proper structure is a major threat to cell function and viability. Consequently, elaborate systems have evolved to protect cells from the deleterious effects of misfolded proteins. The first line of defense against misfolded protein is the molecular chaperones, which associate with nascent polypeptides as they emerge from the ribosome, promoting correct folding and preventing harmful interactions. A large fraction of newly translated proteins nonetheless fails to fold correctly, generating a substantial burden of defective polypeptide (2). These proteins are degraded primarily by the ubiquitin-proteasome system (UPS), a multicomponent system that identifies and degrades unwanted proteins (3). In addition to its role in clearing defective proteins, the UPS carries out selective degradation of many short-lived normal proteins, thereby contributing to the regulation of numerous cellular processes. Failure to detect and eliminate misfolded proteins may contribute to the pathogenesis of neurodegenerative disease. Conversely, it has been suggested that the UPS itself may be a target for toxic proteins (4).
3) Under some circumstances, misfolded proteins may evade the quality control systems designed to promote correct folding and eliminate faulty proteins. When they accumulate in sufficient quantity, misfolded proteins are prone to aggregation. Insoluble aggregates of disease-related proteins may be deposited in microscopically visible inclusions or plaques, the characteristics of which are often disease specific.
4) It has been widely assumed that the formation of intracellular inclusions is a passive process driven by mass-action chemistry, with self-assembly of misfolded monomers into a single growing aggregate. However, this assumption has been challenged by evidence that some intracellular inclusions are formed as part of a physiological response to excess misfolded protein. For example, some mutant proteins are delivered to inclusion bodies by dynein-dependent retrograde transport on microtubules (5). These actively formed inclusions have been designated "aggresomes." Mutant superoxide dismutase, found in some patients with familial amyotrophic lateral sclerosis, and polyglutamine-containing protein, such as generated in Huntington's disease, have been shown to form aggresomes in vitro (4). Inclusion formation by some mutant proteins is regulated by corticosteroids and by the activity of the stress kinase MEKK1, providing further evidence of an active process.
5) In summary: A broad range of neurodegenerative disorders is characterized by neuronal damage that may be caused by toxic, aggregation-prone proteins. As genes are identified for these disorders and cell culture and animal models are developed, it has become clear that a major effect of mutations in these genes is the abnormal processing and accumulation of misfolded protein in neuronal inclusions and plaques. Increased understanding of the cellular mechanisms for disposal of abnormal proteins and of the effects of toxic protein accumulation on neuronal survival may allow the development of rational, effective treatment for these disorders.
References (abridged):
1. A. Aguzzi and A. J. Raeber, Brain Pathol. 8, 695 (1998)
2. U. Schubert, et al., Nature 404, 770 (2000)
3. A. Hershko and A. Ciechanover, Cell 79, 13 (1997)
4. N. F. Bence, R. M. Sampat, R. R. Kopito, Science 292, 1552 (2001)
5. R. R. Kopito, Trends Cell Biol. 10, 524 (2000)
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