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Biomedical subjects

Mark P Mattson

Publications and source records attributed to Mark P Mattson.

At least 109 records · Page 6Linked to original sources
PubMed2003

TERT suppresses apoptotis at a premitochondrial step by a mechanism requiring reverse transcriptase activity and 14-3-3 protein-binding ability.

The catalytic subunit of telomerase (TERT) is a reverse transcriptase (RT) that adds a six-base DNA repeat onto chromosome ends and prevents their shortening during successive cell divisions. Telomerase is associated with cell immortality and cancer, which may by related to the ability of TERT to prevent apoptosis by stabilizing telomeres. However, fundamental information concerning the antiapoptotic function of TERT is lacking, including whether RT activity and/or nuclear localization are required and where telomerase acts to suppress the cell death process. Here, we show that overexpression of wild-type human TERT in HeLa cells, and in a cells lacking TERT but containing the telomerase RNA template, increases their resistance to apoptosis induced by the DNA damaging agent etoposide or the bacterial alkaloid staurosporine. In contrast, TERT mutants with disruptions of either the RT domain or a 14-3-3 binding domain fail to protect cells against apoptosis, and overexpression of TERT in cells lacking the telomerase RNA template is also ineffective in preventing apoptosis. Additional findings show that TERT suppresses apoptosis at an early step before release of cytochrome c and apoptosis-inducing factor from mitochondria. We conclude that both RT activity and 14-3-3 protein binding ability are required for the antiapoptotic function of TERT in tumor cells and that TERT can suppress a nuclear signal(s) that is an essential component of apoptotic cascades triggered by diverse stimuli.

14-3-3 Proteins↗
PubMed2003

Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice.

In addition to neurological deficits, Huntington's disease (HD) patients and transgenic mice expressing mutant human huntingtin exhibit reduced levels of brain-derived neurotrophic factor, hyperglycemia, and tissue wasting. We show that the progression of neuropathological (formation of huntingtin inclusions and apoptotic protease activation), behavioral (motor dysfunction), and metabolic (glucose intolerance and tissue wasting) abnormalities in huntingtin mutant mice, an animal model of HD, are retarded when the mice are maintained on a dietary restriction (DR) feeding regimen resulting in an extension of their life span. DR increases levels of brain-derived neurotrophic factor and the protein chaperone heat-shock protein-70 in the striatum and cortex, which are depleted in HD mice fed a normal diet. The suppression of the pathogenic processes by DR in HD mice suggests that mutant huntingtin promotes neuronal degeneration by impairing cellular stress resistance, and that the body wasting in HD is driven by the neurodegenerative process. Our findings suggest a dietary intervention that may suppress the disease process and increase the life span of humans that carry the mutant huntingtin gene.

Animals↗
PubMed2003

The C-terminal fragment of presenilin 2 triggers p53-mediated staurosporine-induced apoptosis, a function independent of the presenilinase-derived N-terminal counterpart.

Mutations on presenilins are responsible for most of familial forms of Alzheimer's disease. These holoproteins undergo rapid maturation by presenilinase mainly in the endoplasmic reticulum, leading to the production of N- and C-terminal fragments. We show first that overexpression of the presenilinase-derived maturation product of presenilin 2 (CTF-PS2) increases Abeta recovery, the production of which is almost abolished by a caspase 3 inhibitor and increased by staurosporine. This and the observation that the apoptotic inducer staurosporine enhances CTF-PS2 degradation clearly link CTF-PS2 to apoptotic cascade effectors. This prompted us to analyze the putative ability of CTF-PS2 to modulate cell death. CTF-PS2 overexpression decreases cell viability and augments both caspase 3 activity and immunoreactivity. This is accompanied by lowered bcl2-like immunoreactivity and increased poly(ADP-ribose) polymerase cleavage and cytochrome c translocation into the cytosol. Interestingly, CTF-PS2-induced caspase 3 activation is prevented by pifithrin-alpha, a selective blocker of p53 transcriptional activity. On line with the latter data, CTF-PS2 drastically increases p53 immunoreactivity and transcriptional activity. Of most interest is our observation that CTF-PS2 expression also triggers increased caspase 3 activity and immunoreactivity in fibroblasts in which presenilins had been deleted. Therefore, CTF-PS2 could modulate cell death out of the NTF/CTF heterodimeric complex thought to correspond to the biologically functional entity. This is the first direct demonstration that CTF-PS2 could exhibit some of its functions in the absence of the presenilin 2 N-terminal fragment (NTF-PS2) counterpart derived from the presenilinase cleavage.

Animals↗
PubMed2003

Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders.

Folate is a cofactor in one-carbon metabolism, during which it promotes the remethylation of homocysteine -- a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. Dietary folate is required for normal development of the nervous system, playing important roles regulating neurogenesis and programmed cell death. Recent epidemiological and experimental studies have linked folate deficiency and resultant increased homocysteine levels with several neurodegenerative conditions, including stroke, Alzheimer's disease and Parkinson's disease. Moreover, genetic and clinical data suggest roles for folate and homocysteine in the pathogenesis of psychiatric disorders. A better understanding of the roles of folate and homocysteine in neuronal homeostasis throughout life is revealing novel approaches for preventing and treating neurological disorders.

Aging↗
PubMed2003

Mitochondria in cell death: novel targets for neuroprotection and cardioprotection.

Post-mitotic neurons and heart muscle cells undergo apoptotic cell death in a variety of acute and chronic degenerative diseases. The intrinsic pathway of apoptosis involves the permeabilization of mitochondrial membranes, which leads to the release of protease and nuclease activators, and to bioenergetic failure. Mitochondrial permeabilization is induced by a variety of pathologically relevant second messengers, including reactive oxygen species, calcium, stress kinases and pro-apoptotic members of the Bcl-2 family. Several pharmacological agents act on mitochondria to prevent the permeabilization of their membranes, thereby inhibiting apoptosis. Such agents include inhibitors of the permeability transition pore complex (in particular ligands of cyclophilin D), openers of mitochondrial ATP-sensitive or Ca(2+)-activated K(+) channels, and proteins from the Bcl-2 family engineered to cross the plasma membrane. In addition, manipulations that modulate the expression or activity of mitochondrial uncoupling proteins can prevent the death of post-mitotic cells. Such agents hold promise for use in clinical neuroprotection and cardioprotection.

Animals↗
PubMed2003

Age-related trends in gene expression in the chemosensory-nasal mucosae of senescence-accelerated mice.

We have utilized high-density GeneChip oligonucleotide arrays to investigate the use of the senescence-accelerated mouse (SAM) as a biogerontological resource to identify patterns of gene expression in the chemosensory-nasal mucosa. Gene profiling in chronologically young and old mice of the senescence-resistant (SAMR) and senescence-prone (SAMP) strains revealed 133 known genes that were modulated by a three-fold or greater change either in one strain or the other or in both strains during aging. We also identified known genes in our study which based on their encoded proteins were identified as aging-related genes in the aging neocortex and cerebellum of mice as reported by Lee et al. (2000) [Nat. Genet. 25 (2000) 294]. Changes in gene profiles for chemosensory-related genes including olfactory and vomeronasal receptors, sensory transduction-associated proteins, and odor and pheromone transport molecules in the young SAMR and SAMP were compared with age-matched C57BL/6J mice. An analysis of known gene expression profiles suggests that changes in the expression of immune factor genes and genes associated with cell cycle progression and cell death were particularly prominent in the old SAM strains. A preliminary cellular validation study supported the dysregulation of cell cycle-related genes in the old SAM strains. The results of our initial study indicated that the use of the SAM models of aging could provide substantive information leading to a more fundamental understanding of the aging process in the chemosensory-nasal mucosa at the genomic, molecular, and cellular levels.

Aging↗
PubMed2003

Methylation and acetylation in nervous system development and neurodegenerative disorders.

The cytoarchitecture and cellular signaling mechanisms of the nervous system are complex, and this complexity is reflected at the molecular level with more genes being expressed in the nervous system than in any other tissue. Gene expression and protein function in neural cells can be regulated by methylation and acetylation. Studies of mice deficient in enzymes that control DNA methylation and of animals with a dietary deficiency of folate have established critical roles for methylation in development of the nervous system. Various neuronal proteins including histones and tubulin are regulated by acetylation which appears to serve important functions in the development, stability and plasticity of neuronal networks. Some inherited neurological disorders have recently been linked to mutations in genes that regulate DNA methylation, and alterations in DNA and protein methylation and/or acetylation have been documented in studies of age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Manipulations of methylation and acetylation can affect the vulnerability of neurons to degeneration and apoptosis in experimental models of neurodegenerative disorders, suggesting a contribution to altered methylation and acetylation to the disease processes. Interestingly, dietary factors that influence DNA methylation may affect the risk of neurodegenerative disorders, for example, individuals with low dietary folate intake are at increased risk of Alzheimer's and Parkinson's diseases.

Acetylation↗
PubMed2003

Adventures in neural plasticity, aging, and neurodegenerative disorders aboard the CWC beagle.

This article recounts some of the scientific endeavors of Carl W. Cotman (CWC) during his journeys through the cellular circuitry of the mammalian brain. I have selected for consideration his findings that have been an important impetus for my own research; in several cases our different experiments have provided complementary data to support an hypothesis. Three examples are (i) Carl's studies of the roles of glutamate in synaptic transmission and plasticity in the adult brain and my studies of how glutamate regulates neurite outgrowth and cell survival in brain development; (ii) his and our studies of the mechanisms whereby amyloid beta-peptide damages and kills neurons; and (iii) Carl's evidence that physical activity regulates neurotrophin levels in the brain and our evidence that dietary restriction has similar effects and is neuroprotective. In case you have not yet realized how I chose a title for this article it is because Carl has a (very distant) connection with Charles Darwin-Darwin sailed on a vessel called the Beagle and Carl has studied beagle dogs, establishing them as a model for understanding the neurobiology of human brain aging.

Aging↗
PubMed2003

Essential role for integrin linked kinase in Akt-mediated integrin survival signaling in hippocampal neurons.

Activation of integrin receptors in neurons can promote cell survival and synaptic plasticity, but the underlying signal transduction pathway(s) is unknown. We report that integrin signaling prevents apoptosis of embryonic hippocampal neurons by a mechanism involving integrin-linked kinase (ILK) that activates Akt kinase. Activation of integrins using a peptide containing the amino acid sequence EIKLLIS derived from the alpha chain of laminin protected hippocampal neurons from apoptosis induced by glutamate or staurosporine, and increased Akt activity in a beta1 integrin-dependent manner. Transfection of neurons with a plasmid encoding dominant negative Akt blocked the protective effect of the integrin-activating peptide, as did a chemical inhibitor of Akt. Although inhibitors of phosphoinositide-3 (PI3) kinase blocked the protective effect of the peptide, we found no increase in PI3 kinase activity following integrin stimulation suggesting that PI3 kinase was necessary for Akt activity but was not sufficient for the increase in Akt activity following integrin activation. Instead, we show a requirement for ILK in integrin receptor-induced Akt activation. ILK was activated following integrin stimulation and dominant negative ILK blocked integrin-mediated Akt activation and cell survival. Activation of ILK and Akt were also required for neuroprotection by substrate-associated laminin. These results establish a novel pathway that signals cell survival in neurons in response to integrin receptor activation.

Animals↗
PubMed2003

Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms.

Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type-2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cumulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2-deoxy-d-glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and therapeutic approaches for neurodegenerative disorders.

Animals↗
PubMed2003

Involvement of mitochondrial K+ release and cellular efflux in ischemic and apoptotic neuronal death.

We measured and manipulated intracellular potassium (K+) fluxes in cultured hippocampal neurons in an effort to understand the involvement of K+ in neuronal death under conditions of ischemia and exposure to apoptotic stimuli. Measurements of the intracellular K+ concentration using the fluorescent probe 1,3-benzenedicarboxylic acid, 4,4'-[1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetrakis [(acetyloxy) methyl] ester (PBFI) revealed that exposure of neurons to cyanide (chemical hypoxia), glutamate (excitotoxic insult) or staurosporine (apoptotic stimulus) results in efflux of K+ and cell death. Treatment of neurons with 5-hydroxydecanoate (5HD), an inhibitor of mitochondrial K+ channels, reduced K+ fluxes in neurons exposed to each insult and increased the resistance of the cells to death. K+ efflux was attenuated, levels of oxyradicals were decreased, mitochondrial membrane potential was stabilized and release of cytochrome c from mitochondria was attenuated in neurons treated with 5HD. K+ was rapidly released into the cytosol from mitochondria when neurons were exposed to the K+ channel opener, diazoxide, or to the mitochondrial uncoupler, carbonyl cyanide 4(trifluoromethoxy)phenylhydrazone (FCCP), demonstrating that the intramitochondrial K+ concentration is greater than the cytosolic K+ concentration. The release of K+ from mitochondria was followed by efflux through plasma membrane K+ channels. In vivo studies showed that 5HD reduces ischemic brain damage without affecting cerebral blood flow in a mouse model of focal ischemic stroke. These findings suggest that intracellular K+ fluxes play a key role in modulating neuronal oxyradical production and cell survival under ischemic conditions, and that agents that modify K+ fluxes may have therapeutic benefit in stroke and related neurodegenerative conditions.

Animals↗
PubMed2003

Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation.

Tau, a microtubule binding protein, is not only a major component of neurofibrillary tangles in Alzheimer's disease, but also a causative gene for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We show here that an FTDP-17 tau mutation (V337M) in SH-SY5Y cells reduces microtubule polymerization, increases voltage-dependent calcium current (ICa) density, and decreases ICa rundown. The reduced rundown of ICa by V337M was significantly inhibited by nifedipine (L-type Ca channel blocker), whereas omega-conotoxin GVIA (N-type Ca channel blocker) showed smaller effects, indicating that tau mutations affect L-type calcium channel activity. The depolarization-induced increase in intracellular calcium was also significantly augmented by the V337M tau mutation. Treatment with a microtubule polymerizing agent (taxol), an adenylyl cyclase inhibitor, or a protein kinase A (PKA) inhibitor, counteracted the effects of mutant tau on ICa. Taxol also attenuated the Ca2+ response to depolarization in cells expressing mutant tau. Apoptosis in SH-SY5Y cells induced by serum deprivation was exacerbated by the V337M mutation, and nifedipine, taxol, and a PKA inhibitor significantly protected cells against apoptosis. Our results indicate that a tau mutation which decreases its microtubule-binding ability augments calcium influx by depolymerizing microtubules and activating adenylyl cyclase and PKA.

Calcium↗
PubMed2003

Glucagon-like peptide 1 modulates calcium responses to glutamate and membrane depolarization in hippocampal neurons.

Glucagon-like peptide 1 (GLP-1) activates receptors coupled to cAMP production and calcium influx in pancreatic cells, resulting in enhanced glucose sensitivity and insulin secretion. Despite evidence that the GLP-1 receptor is present and active in neurons, little is known of the roles of GLP-1 in neuronal physiology. As GLP-1 modulates calcium homeostasis in pancreatic beta cells, and because calcium plays important roles in neuronal plasticity and neurodegenerative processes, we examined the effects of GLP-1 on calcium regulation in cultured rat hippocampal neurons. When neurons were pre-treated with GLP-1, calcium responses to glutamate and membrane depolarization were attenuated. Whole-cell patch clamp analyses showed that glutamate-induced currents and currents through voltage-dependent calcium channels were significantly decreased in neurons pre-treated with GLP-1. Pre-treatment of neurons with GLP-1 significantly decreased their vulnerability to death induced by glutamate. Acute application of GLP-1 resulted in a transient elevation of intracellular calcium levels, consistent with the established effects of GLP-1 on cAMP production and activation of cAMP response element-binding protein. Collectively, our findings suggest that, by modulating calcium responses to glutamate and membrane depolarization, GLP-1 may play important roles in regulating neuronal plasticity and cell survival.

Animals↗
PubMed2003

Intermittent food deprivation improves cardiovascular and neuroendocrine responses to stress in rats.

Stressful events may trigger disease processes in many different organ systems, with the cardiovascular system being particularly vulnerable. Five-mo-old male rats had ad libitum (AL) access to food or were deprived of food every other day [intermittent food deprivation (IF)] for 6 mo, during which time their heart rate (HR), blood pressure (BP), physical activity and body temperature were measured by radiotelemetry under nonstress and stress (immobilization or cold-water swim) conditions. IF rats had significantly lower basal HR and BP, and significantly lower increases in HR and BP after exposures to the immobilization and swim stressors. Basal levels of adrenocorticotropic hormone (ACTH) and corticosterone were greater in the IF rats. However, in contrast to large stress-induced increases in ACTH, corticosterone and epinephrine levels in AL rats, increases in these hormones in response to repeated immobilization stress sessions were reduced or absent in IF rats. Nevertheless, the IF rats exhibited robust hypothalamic/pituitary and sympathetic neuroendocrine responses to a different stress (swim). The IF treatment improved glucose metabolism, as indicated by lower basal levels of circulating glucose and insulin, but with maintenance of glucose and insulin responses to stress. We concluded that improvements in cardiovascular risk factors and cardiovascular and neuroendocrine stress adaptation occur in response to IF.

Adrenocorticotropic Hormone↗
PubMed2003

RNA interference in biology and medicine.

First discovered in plants the nematode Caenorhabditis elegans, the production of small interfering RNAs (siRNAs) that bind to and induce the degradation of specific endogenous mRNAs is now recognized as a mechanism that is widely employed by eukaryotic cells to inhibit protein production at a post-transcriptional level. The endogenous siRNAs are typically 19- to 23-base double-stranded RNA oligonucleotides, produced from much larger RNAs that upon binding to target mRNAs recruit RNases to a protein complex that degrades the targeted mRNA. Methods for expressing siRNAs in cells in culture and in vivo using viral vectors, and for transfecting cells with synthetic siRNAs, have been developed and are being used to establish the functions of specific proteins in various cell types and organisms. RNA interference methods provide several major advantages over prior methods (antisense DNA or antibody-based techniques) for suppressing gene expression. Recent preclinical studies suggest that RNA interference technology holds promise for the treatment of various diseases. Pharmacologists have long dreamed of the ability to selectively antagonize or eliminate the function of individual proteins--RNAi technology may eventually make that dream a reality.

Animals↗