Showing papers by "Mark P. Mattson published in 2004"
TL;DR: Rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise may soon help in developing effective preventative and therapeutic strategies in Alzheimer's disease.
Abstract: Slowly but surely, Alzheimer's disease (AD) patients lose their memory and their cognitive abilities, and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. Although drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise may soon help in developing effective preventative and therapeutic strategies.
2,850 citations
TL;DR: These findings suggest a sequence of events in the pathogenesis of AD in which Aβ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.
Abstract: Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid β-peptide (Aβ) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to Aβ deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to Aβ induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with α-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Aβ. Our findings suggest a sequence of events in the pathogenesis of AD in which Aβ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.
981 citations
TL;DR: Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging and preserve brain function during aging.
853 citations
TL;DR: It is reported that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease and levels of glial cell line-derived neurotrophic factor were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glialcell line- derived neurotrophic factors in the anti-Parkinson's disease effect of the low-Calorie diet.
Abstract: We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.
343 citations
TL;DR: It is shown that sAPP α increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from Aβ-induced tau phosphorylation and neuronal death and that the elevated expression of transthyretin is mediated by sAPPα and protects APPSw mice from developing many of the neuropathologies observed in AD.
Abstract: Alzheimer's disease (AD) may be caused by the abnormal processing of the amyloid precursor protein (APP) and the accumulation of beta-amyloid (Abeta). The amyloid precursor protein can be proteolytically cleaved into multiple fragments, many of which have distinct biological actions. Although a high level of Abeta can be toxic, the alpha-secretase cleaved APP (sAPPalpha) is neuroprotective. However, the mechanism of sAPPalpha protection is unknown. Here, we show that sAPPalpha increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from Abeta-induced tau phosphorylation and neuronal death. Antibody interference and small interfering RNA knock-down demonstrate that the sAPPalpha-driven expression of transthyretin and insulin-like growth factor 2 is necessary for protection against Abeta-induced neuronal death. Mice overexpressing mutant APP possess high levels of sAPPalpha and transthyretin and do not develop the tau phosphorylation or neuronal loss characteristic of human AD. Chronic infusion of an antibody against transthyretin into the hippocampus of mice overexpressing APP with the Swedish mutation (APP(Sw)) leads to increased Abeta, tau phosphorylation, and neuronal loss and apoptosis within the CA1 neuronal field. Therefore, the elevated expression of transthyretin is mediated by sAPPalpha and protects APP(Sw) mice from developing many of the neuropathologies observed in AD.
303 citations
TL;DR: The ageing process and its associated diseases all involve perturbed energy metabolism, oxidative damage, and an impaired ability of the organism and its cells to cope with adversity, so it is proposed that some specific signaling pathways in the brain may be important determinants of health during ageing.
266 citations
TL;DR: Levels of ceramide, sphingomyelin, and hydroxynonenal (HNE) are significantly increased in brain tissues and cerebrospinal fluid of HIVD patients, suggesting that HIV‐1 infection may promote a lipid imbalance in neural cells, resulting in an overproduction of Ceramide and consequent cellular dysfunction and death.
Abstract: Infection by the human immunodeficiency virus type 1 (HIV-1) often results in neurological dysfunction including HIV dementia (HIVD). Alterations in cytokine and redox balance are thought to play important roles in the pathogenesis of HIVD, but the specific mechanisms underlying neuronal dysfunction and death are unknown. Activation of cytokine receptors and oxidative stress can induce the production of ceramide from membrane sphingomyelin, and recent findings suggest that ceramide is an important mediator of a form of programmed cell death called apoptosis. We now report that levels of ceramide, sphingomyelin, and hydroxynonenal (HNE) are significantly increased in brain tissues and cerebrospinal fluid of HIVD patients. Exposure of cultured neurons to the neurotoxic HIV proteins gp120 and Tat resulted in increased cellular levels of sphingomyelin, ceramide, and HNE. The ceramide precursor palmitoyl-CoA sensitized neurons to Tat and gp120 toxicity, whereas an inhibitor of ceramide production reduced Tat and gp120-induced increases of ceramide and HNE and protected the neurons from Tat and gp120-induced death. These results suggest that HIV-1 infection may promote a lipid imbalance in neural cells, resulting in an overproduction of ceramide and consequent cellular dysfunction and death.
246 citations
TL;DR: An important role is suggested for Notch signaling in a form of synaptic plasticity known to be associated with learning and memory processes in mice with reduced Notch levels.
Abstract: During development of the nervous system, the fate of stem cells is regulated by a cell surface receptor called Notch. Notch is also present in the adult mammalian brain; however, because Notch null mice die during embryonic development, it has proven difficult to determine the functions of Notch. Here, we used Notch antisense transgenic mice that develop and reproduce normally, but exhibit reduced levels of Notch, to demonstrate a role for Notch signaling in synaptic plasticity. Mice with reduced Notch levels exhibit impaired long-term potentiation (LTP) at hippocampal CA1 synapses. A Notch ligand enhances LTP in normal mice and corrects the defect in LTP in Notch antisense transgenic mice. Levels of basal and stimulation-induced NF-κB activity were significantly decreased in mice with reduced Notch levels. These findings suggest an important role for Notch signaling in a form of synaptic plasticity known to be associated with learning and memory processes.
231 citations
TL;DR: The data from animal studies suggest that it may be possible to reduce the risk for age-related neurodegenerative disorders through dietary and behavioral modifications that act by promoting neuronal plasticity and survival.
Abstract: It is well established that when most types of cells, including neurons, are exposed to a mild stress they increase their ability to resist more severe stress. This “preconditioning” phenomenon involves up-regulation of genes that encode cytoprotective proteins such as heat-shock proteins and growth factors. We found that a similar beneficial cellular stress response can be induced in neurons throughout the brain by a “meal-skipping” dietary restriction (DR) regimen in rats and mice. DR is effective in protecting neurons and improving functional outcome in models of stroke, Alzheimer’s, Parkinson’s and Huntington’s diseases. DR induces an increase in the levels of brain-derived neurotrophic factor (BDNF) and heat-shock proteins in neurons. DR also stimulates neurogenesis in the hippocampus, and BDNF plays a role in this effect of DR. Physical exercise and environmental enrichment are two other manipulations that have been shown to induce BDNF expression in the brain, presumably because it is a mild cellular stress. When taken together with epidemiological and clinical studies in humans, the data from animal studies suggest that it may be possible to reduce the risk for age-related neurodegenerative disorders through dietary and behavioral modifications that act by promoting neuronal plasticity and survival.
145 citations
TL;DR: A pivotal role is established for gap junction-mediated intercellular communication in determining the proliferation and survival of mouse neural progenitor cells (NPCs) and gap junctional communication is both necessary and sufficient to maintain NPCs in a self-renewing state.
122 citations
TL;DR: It is reported that Herp is present in neurons in the developing and adult brain, and that it is regulated in neurons by ER stress; sublethal levels of ER stress increase Herp levels, whereas higher doses decrease HerP levels and induce apoptosis.
TL;DR: To forestall the neurodegenerative process, specific targets to inhibit are chosen that are at pivotal rate‐limiting steps within the pathological cascade, including TNF‐α, p53, and GLP‐1 receptor.
Abstract: Owing to improving preventative, diagnostic, and therapeutic measures for cardiovascular disease and a variety of cancers, the average ages of North Americans and Europeans continue to rise. Regrettably, accompanying this increase in life span, there has been an increase in the number of individuals afflicted with age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and stroke. Although different cell types and brain areas are vulnerable among these, each disorder likely develops from activation of a common final cascade of biochemical and cellular events that eventually lead to neuronal dysfunction and death. In this regard, different triggers, including oxidative damage to DNA, the overactivation of glutamate receptors, and disruption of cellular calcium homeostasis, albeit initiated by different genetic and/or environmental factors, can instigate a cascade of intracellular events that induce apoptosis. To forestall the neurodegenerative process, we have chosen specific targets to inhibit that are at pivotal rate-limiting steps within the pathological cascade. Such targets include TNF-alpha, p53, and GLP-1 receptor. The cytokine TNF-alpha is elevated in Alzheimer's disease, Parkinson's disease, stroke, and amyotrophic lateral sclerosis. Its synthesis can be reduced via posttranscriptional mechanisms with novel analogues of the classic drug, thalidomide. The intracellular protein and transcription factor, p53, is activated by the Alzheimer's disease toxic peptide, Abeta, as well as by excess glutamate and hypoxia to trigger neural cell death. It is inactivated by novel tetrahydrobenzothiazole and -oxazole analogues to rescue cells from lethal insults. Stimulation of the glucagon-like peptide-1 receptor (GLP-1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults.
TL;DR: It is suggested that ES cells are immortal because these pathways are tightly regulated and related to these pathways in embryonic stem (ES) cells are summarized.
Abstract: Most mammalian cells when placed in culture will undergo a limited number of cell divisions before entering an unresponsive non-proliferating state termed senescence However, several pathways that are activated singly or in concert can allow cells to bypass senescence at least for limited periods These include the telomerase pathway required to maintain telomere ends, the p53 and Rb pathways required to direct senescence in response to DNA damage, telomere shortening and mitogenic signals, and the insulin-like growth factor--Akt pathway that may regulate lifespan and cell proliferation In this review, we summarize recent findings related to these pathways in embryonic stem (ES) cells and suggest that ES cells are immortal because these pathways are tightly regulated
TL;DR: Administration of paroxetine suppresses the neurodegenerative process and increases the survival of huntingtin mutant mice, an animal model of Huntington's disease (HD), suggesting a potential for such antidepressant drugs in the treatment of presymptomatic and symptomatic HD patients.
Abstract: We report that administration of paroxetine, a widely prescribed antidepressant drug that acts by inhibiting reuptake of the neurotransmitter serotonin, suppresses the neurodegenerative process and increases the survival of huntingtin mutant mice, an animal model of Huntington's disease (HD). Paroxetine attenuated motor dysfunction and body weight loss and improved glucose metabolism in the HD mice. Paroxetine was beneficial when treatment was initiated before or after the onset of motor dysfunction, suggesting a potential for such antidepressant drugs in the treatment of presymptomatic and symptomatic HD patients.
TL;DR: Recent findings suggest the possibility that infectious agents may increase the risk of common age-related neurodegenerative disorders such as Alzheimer’s disease and Parkinson's disease, amyotrophic lateral sclerosis (ALS) and stroke.
TL;DR: HIV dementia patients with an APOE4 genotype may be sensitized to neural insults because of dysregulations in lipid metabolism, which is associated with worse prognoses in numerous neurodegenerative conditions, including HIV dementia.
Abstract: Background: Polymorphisms in apolipoprotein E have been associated with worse prognoses in numerous neurodegenerative conditions, including HIV dementia (HIVD). Despite these correlative observations, there has been little evidence suggesting a mechanism whereby the expression of ApoE4 renders neurons susceptible to insult. Methods: Electrospray ionization tandem mass spectrometry was used to quantify levels of sphingolipids and sterols in brains of HIVD patients. Data were stratified according to APOE genotype. Results: The authors found evidence of dysregulated lipid and sterol metabolism in HIVD patients with an APOE4 genotype. They also found elevations of sphingomyelin, ceramide, and cholesterol in the medial frontal cortex, parietal cortex, and cerebellum of HIVD patients with an APOE3/4 or APOE4/4 genotype compared with HIVD patients with an APOE3/3 genotype. There was no difference in the number of astrocytes or activated microglia in any brain region of the two patient populations, suggesting that modification of lipid metabolism in HIVD patients with an APOE4 genotype was not the result of increased CNS inflammation. Conclusions: HIV dementia patients with an APOE4 genotype may be sensitized to neural insults because of dysregulations in lipid metabolism.
TL;DR: While reduced iron may provide protection against PD-inducing insults such as MPTP, the role of iron in the synthesis of DA and neuronal survival should be considered, particularly in the development of iron-chelating agents to be used chronically in the clinical setting.
TL;DR: Levels of UNG expression were increased in brains of cystathionine β-synthase knockout mice, a model for hyperhomocysteinemia, suggesting that one-carbon metabolism impairment and uracil misincorporation can induce the up-regulation ofUNG expression.
TL;DR: It is concluded that improvements in some cardiovascular risk factors and stress adaptation in rats maintained on a 2-DG-supplemented diet are associated with reduced neuroendocrine responses to the stressors.
Abstract: Dietary restriction and physical exercise can enhance stress resistance and reduce the risk of cardiovascular disease. We investigated the effects of dietary supplementation with 2-deoxy-d-glucose (2-DG), a glucose analog that limits glucose availability at the cellular level, on cardiovascular and neuroendocrine responses to stress in rats. Young adult male Sprague-Dawley rats were implanted with telemetry probes to monitor blood pressure (BP), heart rate, body temperature, and body movements. These variables were measured at designated times during a 6-mo period in rats fed control and 2-DG-supplemented (0.4% 2-DG, fed ad libitum on a schedule of 2 days on the diet and 1 day off the diet) diets during unperturbed conditions and during and after immobilization stress or cold-water swim stress. Rats fed the 2-DG diet exhibited significant reductions in resting BP, attenuated BP responses during stress, and accelerated recovery to baseline after stress. Plasma concentrations of ACTH and corticosterone were elevated under nonstress conditions in rats fed the 2-DG diet and exhibited differential responses to single (enhanced response) and multiple (reduced response) stress sessions compared with rats fed control rat chow ad libitum. The 2-DG diet improved glucose metabolism, as indicated by decreased concentrations of blood glucose and insulin under nonstress conditions, but glucose and insulin responses to stress were maintained. We conclude that improvements in some cardiovascular risk factors and stress adaptation in rats maintained on a 2-DG-supplemented diet are associated with reduced neuroendocrine responses to the stressors.
TL;DR: It is shown that ATP enhances long-term potentiation (LTP), and P2X receptor antagonists inhibit this ATP effect, but do not affect paired pulse facilitation (PPF) in rat hippocampal slices, indicating that presynaptic P2Y receptors also play an important role in neuronal plasticity.
Abstract: Although ATP is reported to modulate synaptic plasticity, the mechanism of action of ATP on synaptic transmission is not fully understood. Here we show that ATP enhances long-term potentiation (LTP), and P2X receptor antagonists inhibit this ATP effect, but do not affect paired pulse facilitation (PPF) in rat hippocampal slices. ATP rapidly increases intracellular calcium, and P2X receptor antagonists inhibit this increase in cultured dissociated neurons. These results indicate that ATP enhances LTP via activation of postsynaptic P2X receptors. A pertussis toxin-sensitive G-protein inhibitor significantly attenuates PPF, although it does not affect LTP, indicating that presynaptic P2Y receptors also play an important role in neuronal plasticity. We conclude that ATP modulates synaptic plasticity via dual effects on pre- and post-synaptic mechanisms.
Book•
01 Oct 2004
TL;DR: From Intramolecular Asymmetries to Raft Assemblies: A Short Guide for the Puzzled in Lipidomics Ephraim Yavin and Annette Brand Regulatory Aspects of Membrane Microdomain (Raft) Dynamics in Live Cells: A Biophysical Approach Janos Matko and Janos Szollosi Lipid Raft Membranes Skeletons.
Abstract: From Intramolecular Asymmetries to Raft Assemblies: A Short Guide for the Puzzled in Lipidomics Ephraim Yavin and Annette Brand Regulatory Aspects of Membrane Microdomain (Raft) Dynamics in Live Cells: A Biophysical Approach Janos Matko and Janos Szollosi Lipid Raft Membrane Skeletons Elizabeth J. Luna, Thomas Nebl, Norio Takizawa, and Jessica L. Crowley Role of Cholesterol in Membrane Microdomain Signaling Christopher J. Fielding Raft Lipid Metabolism in Relation to Alkyl-Lysophospholipid-Induced Apoptosis Arnold H. van der Luit, Marcel Verheij, and Wim J. van Blitterswijk Role of Lipid Rafts in Signal Transduction and Synaptic Plasticity of Neural Cells Markus Delling and Melitta Schachner Role of Rafts in Virus Fusion and Budding Wu Ou and Jonathan Silver Alterations in Raft Lipid Metabolism in Aging and Neurodegenerative Disorders Mark P. Mattson, Roy G. Cutler, and Norman J. Haughey Caveolin and Cancer: A Complex Relationship Mordechai Liscovitch, Elke Burgermeister, Neeru Jain, Dana Ravid, Maria Shatz, and Lilach Tencer Dietary Modulation of Lipid Rafts: Implications for Disease Prevention and Treatment Mark P. Mattson Index
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TL;DR: mental decline is inseparable from aging and hencethat life inevitably ends in dementia, although ‘veryfortunately, few of the human species arrive’ (Pythagoras, cited from Ref. [2]) to such an advancedage.
TL;DR: Bone marrow transplantation can be used to introduce genetically modified BMM into the adult mouse brain to reveal the functions of one or more BMM genes in neuronal injury responses, suggesting a pivotal role for BMM nitric oxide production in excitotoxic neuronal damage.
Abstract: The signaling mechanisms by which brain macrophages and microglia (BMM) respond to injury and disease, and how their responses affect neurodegenerative processes are largely unknown. Here we show that bone marrow transplantation can be used to introduce genetically modified BMM into the adult mouse brain to reveal the functions of one or more BMM genes in neuronal injury responses. Mice in which endogenous BMM were replaced with cells from mice lacking p55 and p75 tumor necrosis factor (TNF) receptors exhibit increased vulnerability of hippocampal neurons to excitotoxic injury suggesting a role for TNF signaling in BMM in the excitotoxic injury response. Neurons in the brains of mice with BMM lacking nitric oxide synthase exhibit reduced protein nitration and are less vulnerable to excitotoxic damage, indicating a pivotal role for BMM nitric oxide production in excitotoxic neuronal damage.
TL;DR: Results indicate that the AA‐evoked increase in ChAT activity in spinal cord neurons is mediated by PKC, presumably at the transcriptional level.
Abstract: Arachidonic acid (AA) plays an important role as a signaling factor in the CNS. Therefore, exposure to AA may affect cholinergic neurons in the spinal cord. To test this hypothesis, mRNA expression and activity of choline acetyltransferase (ChAT) was measured in cultured spinal cord neurons treated with increasing concentrations (0.1–10 µm) of AA. Exposure to AA increased mRNA levels and activity of ChAT in dose- and time-dependent manners. The most marked effect of AA on ChAT expression was observed in spinal cord neurons treated with 10 µm AA for 1 h. To study the mechanisms associated with these effects, ChAT mRNA levels and activity were measured in cultured spinal cord neurons exposed to AA and inhibitors of protein kinase C (PKC), such as 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dichloride (H-7) and chelerythrine. Inhibition of PKC completely prevented an AA-induced increase in ChAT expression. In addition, exposure of spinal cord neurons to phorbol-12-myristate-13-acetate (PMA), an activator of PKC, mimicked AA-induced stimulation of ChAT activity. The AA-mediated increase in ChAT mRNA levels and activity was also prevented by treatments with EGTA, indicating the role of calcium metabolism in induction of this enzyme. In contrast, treatments with 7-nitroindazole (7-NI, a specific inhibitor of neuronal nitric oxide synthase), sodium vanadate (NaV, a non-specific inhibitor of phosphatases), and N-acetyl-cysteine (NAC, an antioxidant) had no effect on AA-induced changes in ChAT activity. The protein synthesis inhibitor cycloheximide completely blocked AA-mediated increase in ChAT activity. These results indicate that the AA-evoked increase in ChAT activity in spinal cord neurons is mediated by PKC, presumably at the transcriptional level.
TL;DR: New work in this issue indicates that Syncytin is activated in multiple sclerosis astrocytes and microglia, contributing to the inflammation-induced myelin destruction that causes disease symptoms.
Abstract: Syncytin is a viral envelope protein encoded in the human genome. New work in this issue indicates that it is activated in multiple sclerosis astrocytes and microglia, contributing to the inflammation-induced myelin destruction that causes disease symptoms.
TL;DR: It is reported that systemic administration of kainic acid rapidly elevates expression of mRNA encoding neuronal apoptosis inhibitor protein (NAIP) in the hippocampus and that this increase does not occur in mice that lack TNF receptors, suggesting that induction of the naip gene may contribute to the neuroprotective properties of TNF.
TL;DR: The rate constant α in the Gompertz equation on aging to intrinsic as opposed to environmental mechanisms of senescence based on the analysis of genes modulated during aging in the olfactory mucosa was related to the variability in the mean hybridization signals as determined by the two‐sided t‐test.
Abstract: We utilized high-density Affymetrix oligonucleotide arrays to investigate gene expression in the olfactory mucosae of near age-matched aging senescence-accelerated mice (SAM). The senescence-prone (SAMP) strain has a significantly shorter lifespan than does the senescence-resistant (SAMR) strain. To analyze our data, we applied biostatistical methods that included a correlation analysis to evaluate sources of methodologic and biological variability; a two-sided t-test to identify a subpopulation of Present genes with a biologically relevant P-value <0.05; and a false discovery rate (FDR) analysis adjusted to a stringent 5% level that yielded 127 genes with a P-value of <0.001 that were differentially regulated in near age-matched SAMPs (SAMP-Os; 13.75 months) compared to SAMRs (SAMR-Os, 12.5 months). Volcano plots related the variability in the mean hybridization signals as determined by the two-sided t-test to fold changes in gene expression. The genes were categorized into the six functional groups used previously in gene profiling experiments to identify candidate genes that may be relevant for senescence at the genomic and cellular levels in the aging mouse brain (Lee et al. [2000] Nat Genet 25:294–297) and in the olfactory mucosa (Getchell et al. [2003] Ageing Res Rev 2:211–243), which serves several functions that include chemosensory detection, immune barrier function, xenobiotic metabolism, and neurogenesis. Because SAMR-Os and SAMP-Os have substantially different median lifespans, we related the rate constant α in the Gompertz equation on aging to intrinsic as opposed to environmental mechanisms of senescence based on our analysis of genes modulated during aging in the olfactory mucosa. © 2004 Wiley-Liss, Inc.
TL;DR: The engaging tale related by Andrew Brown describes how C. elegans came to be the first multicellular organism to be sequenced in the genome race — a research project that garnered a Nobel Prize for illuminating genetic regulation and programmed cell death in the process.
Abstract: In September of 1998, the press announced with great fanfare the completion of the first sequence of a multicellular organism. It was not the human genome, which would be completed two years later, or the mouse, rat, or fruit fly genomes. Rather, the 1998 announcement concerned a more modest organism, Caenorhabditis elegans, a small soil-dwelling nematode found in temperate climates worldwide that feeds on bacteria and slime mold. How C. elegans came to be the first multicellular organism to be sequenced in the genome race — a research project that garnered a Nobel Prize for illuminating genetic regulation and programmed cell death in the process — is the engaging tale related by Andrew Brown.
The book opens in the early 1960s, with Sydney Brenner and others at the Laboratory of Molecular Biology (LMB) in Cambridge, United Kingdom, debating their visions for the future path of molecular biology. Brenner believed that a molecular approach could be applied to studies of development and nervous system function and boldly proposed the genetic analysis of a simple eukaryote to accomplish these goals. The organism he ultimately chose for these studies, C. elegans, was selected for its rapid development, robust reproduction, anatomic transparency, and small size, conducive for detailed microscopic analysis.
Brown’s description of the worm project reveals that Brenner had endeavored to construct a complete map of the worm on at least three different levels. The first level was the genetic map. This required the organism’s genetic deconstruction. Brenner himself, along with the talented scientists he recruited, used chemical mutagenesis to isolate numerous mutations affecting development and movement. Following genetic techniques used in his earlier phage studies, Brenner could analyze the phenotypes of animals carrying combinations of these mutations to construct a genetic map for C. elegans. This genetic map shows the relative positions of the genes that led to the mutant phenotypes.
The second level of the map was an unprecedented four-dimensional description of embryonic and nervous system development. John White and Eileen Southgate, at LMB, described the anatomy and connectivity of the worm’s 302-cell nervous system. Brown vividly presents the painstaking detail with which White and Southgate assembled electron micrographs from serial sections of the worm to determine the animal’s nervous system connectivity. This map has allowed researchers to study specific neural pathways in detail. For example, scientists can identify the neural pathway by which signals from sensory neurons lead to a behavioral output, such as movement. Brown goes on to relate the work of John Sulston, at LMB, who described the complete developmental lineage of C. elegans: it is invariant, so that a specific cell’s developmental fate is predictable. By comparing the lineage with the nervous system anatomy, Sulston and White could determine the developmental fates of every neuron precursor. The lineage analysis also revealed that certain cells were predictably lost during development. Studies of these lost cells by Bob Horvitz at LMB and, later, MIT led to the discovery of apoptosis in C. elegans and other species.
The third level of the map was the genome sequence, realized in 1998. The final chapters of Brown’s book describe the scientific and political challenges faced by C. elegans researchers who worked on this task. Sulston and Alan Coulson at the LMB and Bob Waterston at Washington University in St. Louis coordinated this process. First, Sulston and Coulson assembled a physical map of the genome from cosmid and YAC libraries. They then coordinated the physical and genetic maps, allowing scientists to identify the precise physical position of cloned genes. With the physical map in hand, along with the cosmid and YAC libraries used in its construction, C. elegans was well positioned to be a trial genome project in preparation for sequencing the full human genome.
The biomedical sciences have made major advances in understanding human disease from studies of C. elegans. For example, Bcl-2 family members and caspases were first discovered in the worm. These proteins control the process of apoptosis, a form of cell death that is abnormally activated in many degenerative diseases and that is abnormally suppressed in many types of cancer. Drugs that target mammalian homologs of the worm proteins to inhibit or induce apoptosis are currently being developed for use in various human diseases. C. elegans is also proving to be a powerful tool to discover molecular mechanisms that regulate fundamental processes such as post-transcriptional gene silencing — a process called RNA interference that is now being exploited to develop novel gene-specific therapies for diseases.
Brown relates this engaging story in accessible language for scientists and laypeople alike. In an era when scientific storytelling has become commonplace, this book stands out for its lesson on independent thought. Scientists preferring more sophisticated organisms often challenged the worm project for its humbleness. Yet C. elegans has become one of the best-understood and most powerful systems in biology, due to the diligence and originality of the scientists described. Brown clearly relates the perseverance and vision of the first generation of worm scientists that led to these accomplishments.
01 Jan 2004
TL;DR: The nervous system protects itself against excitotoxicity by deploying multiple antiexcitotoxic signaling pathways including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins and inhibitor of apoptosis proteins.
Abstract: All neurons in the central nervous system of mammals express receptors for the excitatory amino acid glutamate. Although glutamatergic neurotransmission is therefore essential for the functioning of neuronal circuits in the brain and spinal cord, under certain conditions activation of glutamate receptors can trigger the death of neurons. Such excitotoxicity most often occurs when cells are coincidentally subjected to reduced levels of oxygen or glucose, increased levels of oxidative stress, trauma, or exposure to toxins or other pathogenic agents. Excitotoxicity is mediated by excessive calcium influx and release from internal organelles, oxyradical production and the activation of a form of programmed cell death called apoptosis. Proteins such as p53, Bax and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases such as caspase-3. Essentially all subcellular compartments, including the endoplasmic reticulum, mitochondria and nucleus are involved in the excitotoxic process. Excitotoxic cascades are initiated in postsynaptic dendrites where glutamate receptors are most highly concentrated, and may either cause local degeneration or plasticity of those synapses or may propagate the signals to the cell body resulting in cell death. The nervous system protects itself against excitotoxicity by deploying multiple antiexcitotoxic signaling pathways including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins and inhibitor of apoptosis proteins. A rapid accumulation of information on the molecular underpinnings of the excitotoxic process is leading to the development of novel therapeutic approaches for neurodegenerative disorders, as well as unexpected insight into mechanisms of synaptic plasticity.