RESUMO
We have examined the role of somatic mitochondrial DNA (mtDNA) mutations in human ageing by quantitating the accumulation of the common 4977 nucleotide pair (np) deletion (mtDNA4977) in the cortex, putamen and cerebellum. A significant increase in the mtDNA4977 deletion was seen in elderly individuals. In the cortex, the deleted to total mtDNA ratio ranged from 0.00023 to 0.012 in 67-77 year old brains and up to 0.034 in subjects over 80. In the putamen, the deletion level ranged from 0.0016 to 0.010 in 67 to 77 years old up to 0.12 in individuals over the age of 80. The cerebellum remained relatively devoid of mtDNA deletions. Similar changes were observed with a different 7436 np deletion. These changes suggest that somatic mtDNA deletions might contribute to the neurological impairment often associated with ageing.
Assuntos
Envelhecimento/genética , Encéfalo/metabolismo , DNA Mitocondrial/genética , Deleção de Sequência , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Sequência de Bases , Dano ao DNA , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Fosforilação Oxidativa , Distribuição TecidualRESUMO
The discovery that some cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) has focused much attention on the function of SOD1 as related to motor neuron survival. Here we describe the creation and characterization of mice completely deficient for this enzyme. These animals develop normally and show no overt motor deficits by 6 months in age. Histological examination of the spinal cord reveals no signs of pathology in animals 4 months in age. However Cu/Zn SOD-deficient mice exhibit marked vulnerability to motor neuron loss after axonal injury. These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.
Assuntos
Axônios/fisiologia , Neurônios Motores/fisiologia , Medula Espinal/patologia , Superóxido Dismutase/deficiência , Superóxido Dismutase/genética , Animais , Axônios/patologia , Nervo Facial/citologia , Nervo Facial/patologia , Nervo Facial/fisiologia , Glutationa/metabolismo , Peroxidação de Lipídeos , Camundongos , Camundongos Mutantes , Neurônios Motores/patologia , Recombinação Genética , Valores de Referência , Medula Espinal/citologia , Superóxido Dismutase/metabolismoRESUMO
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxicity in mice. We now show that 7-NI protects against profound striatal dopamine depletions and loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated baboons. Furthermore, 7-NI protected against MPTP-induced motor and frontal-type cognitive deficits. These results strongly implicate a role of nitric oxide in MPTP neurotoxicity and suggest that inhibitors of neuronal NOS might be useful in treating Parkinson's disease.
Assuntos
Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Neurônios/enzimologia , Óxido Nítrico Sintase/antagonistas & inibidores , Doença de Parkinson Secundária/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Hipocinesia , Masculino , Atividade Motora , Exame Neurológico , Neurônios/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Papio , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/enzimologia , Substância Negra/efeitos dos fármacos , Substância Negra/enzimologia , Gravação de VideoteipeRESUMO
Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A human SOD1 mutation have altered electron transport enzymes, and expression of the mutant enzyme in vitro results in a loss of mitochondrial membrane potential and elevated cytosolic calcium concentration. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. We found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Creatina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Alanina/genética , Alanina/fisiologia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Creatina/administração & dosagem , Creatina/metabolismo , Modelos Animais de Doenças , Glicina/genética , Glicina/fisiologia , Humanos , Camundongos , Camundongos Transgênicos , Atividade Motora , Músculo Esquelético/fisiopatologia , Neurônios/citologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/fisiologia , Superóxido Dismutase-1 , Tirosina/análogos & derivados , Tirosina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
BACKGROUND: Huntington's disease (HD) is associated with impaired energy metabolism in the brain. Creatine kinase (CK) catalyzes ATP-dependent phosphorylation of creatine (Cr) into phosphocreatine (PCr), thereby serving as readily available high-capacity spatial and temporal ATP buffering. OBJECTIVE: Substantial evidence supports a specific role of the Cr/PCr system in neurodegenerative diseases. In the brain, the Cr/PCr ATP-buffering system is established by a concerted operation of the brain-specific cytosolic enzyme BB-CK and ubiquitous mitochondrial uMt-CK. It is not yet established whether the activity of these CK isoenzymes is impaired in HD. METHODS: We measured PCr, Cr, ATP and ADP in brain extracts of 3 mouse models of HD - R6/2 mice, N171-82Q and HdhQ(111) mice - and the activity of CK in cytosolic and mitochondrial brain fractions from the same mice. RESULTS: The PCr was significantly increased in mouse HD brain extracts as compared to nontransgenic littermates. We also found an approximately 27% decrease in CK activity in both cytosolic and mitochondrial fractions of R6/2 and N171-82Q mice, and an approximately 25% decrease in the mitochondria from HdhQ(111) mice. Moreover, uMt-CK and BB-CK activities were approximately 63% lower in HD human brain samples as compared to nondiseased controls. CONCLUSION: Our findings lend strong support to the role of impaired energy metabolism in HD, and point out the potential importance of impairment of the CK-catalyzed ATP-buffering system in the etiology of HD.
Assuntos
Encéfalo/enzimologia , Creatina Quinase Forma BB/metabolismo , Doença de Huntington/enzimologia , Animais , Química Encefálica , Cromatografia Líquida de Alta Pressão , Creatina Quinase Forma BB/análise , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Fosfocreatina/análise , Fosfocreatina/metabolismoRESUMO
Somatostatin receptors in rat brain, pituitary, and pancreas were labeled with two radioiodinated analogs of somatostatins 14 and 28. Two cyclic analogs of somatostatin, SMS201-995 and cyclo(Ala-Cys-Phe-D-Trp-Lys-Thr-Cys), showed biphasic displacement of binding to somatostatin receptors by these radioligands. In contrast, all other somatostatin analogs, including somatostatin-14, competed for the receptor sites with monophasic displacement of radioligand receptor binding. Thus two types of somatostatin receptors were identified. It was found that the pituitary and pancreas have predominantly one type of somatostatin receptor whereas the brain has both, and that different regions of the brain have various proportions of the two types. These findings suggest methods to characterize other types of somatostatin receptors subserving somatostatin's diverse physiological functions, including a potential role in cognitive function and extrapyramidal motor system control.
Assuntos
Peptídeos Cíclicos , Receptores de Superfície Celular/classificação , Somatostatina/análogos & derivados , Animais , Ligação Competitiva , Encéfalo/metabolismo , Cinética , Pâncreas/metabolismo , Hipófise/metabolismo , Ensaio Radioligante , Ratos , Receptores de Superfície Celular/metabolismo , Receptores de SomatostatinaRESUMO
A distinct subpopulation of striatal aspiny neurons, containing the enzyme nicotinamide adenine dinucleotide phosphate diaphorase, is preserved in the caudate nucleus in Huntington's disease. Biochemical assays confirmed a significant increase in the activity of this enzyme in both the caudate nucleus and putamen in postmortem brain tissue from patients with this disease. The resistance of these neurons suggests that the gene defect in Huntington's disease may be modifiable by the local biochemical environment. This finding may provide insight into the nature of the genetically programmed cell death that is a characteristic of the disease.
Assuntos
Corpo Estriado/patologia , Doença de Huntington/patologia , Neurônios/patologia , Adulto , Idoso , Núcleo Caudado/enzimologia , Núcleo Caudado/patologia , Corpo Estriado/enzimologia , Humanos , Doença de Huntington/enzimologia , Pessoa de Meia-Idade , NADPH Desidrogenase/análise , Proteínas do Tecido Nervoso/análise , Neurônios/enzimologia , Neuropeptídeo YRESUMO
Somatostatin receptor concentrations were measured in patients with Alzheimer's disease and controls. In the frontal cortex (Brodmann areas 6, 9, and 10) and temporal cortex (Brodmann area 21), the concentrations of somatostatin in receptors in the patients were reduced to approximately 50 percent of control values. A 40 percent reduction was seen in the hippocampus, while no significant changes were found in the cingulate cortex, postcentral gyrus, temporal pole, and superior temporal gyrus. Scatchard analysis showed a reduction in receptor number rather than a change in affinity. Somatostatin-like immunoreactivity was significantly reduced in both the frontal and temporal cortex. Somatostatin-like immunoreactivity was linearly related to somatostatin-receptor binding in the cortices of Alzheimer's patients. These findings may reflect degeneration of postsynaptic neurons or cortical afferents in the patients' cerebral cortices. Alternatively, decreased somatostatin-like immunoreactivity in Alzheimer's disease might indicate increased release of somatostatin and down regulation of postsynaptic receptors.
Assuntos
Doença de Alzheimer/metabolismo , Córtex Cerebral/análise , Receptores de Superfície Celular/análise , Adulto , Idoso , Cromatografia Líquida de Alta Pressão , Feminino , Lobo Frontal/análise , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/fisiologia , Radioimunoensaio , Receptores de Somatostatina , Somatostatina/metabolismo , Somatostatina/fisiologia , Lobo Temporal/análiseRESUMO
Transgenic mice developing beta-amyloid (Abeta) plaques are advancing experimental treatment strategies for Alzheimer's disease. The metal chelator, clioquinol, is reported by Cherny et al. (2001) to reduce Abeta plaques, presumably by chelation of Abeta-associated zinc and copper. This and other recent Abeta-modulating treatment approaches are discussed.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Quelantes/farmacologia , Clioquinol/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Placa Amiloide/metabolismo , Placa Amiloide/patologiaRESUMO
A trinucleotide repeat (CAG) expansion in the huntingtin gene causes Huntington's disease (HD). In brain tissue from HD heterozygotes with adult onset and more clinically severe juvenile onset, where the largest expansions occur, a mutant protein of equivalent intensity to wild-type huntingtin was detected in cortical synaptosomes, indicating that a mutant species is synthesized and transported with the normal protein to nerve endings. The increased size of mutant huntingtin relative to the wild type was highly correlated with CAG repeat expansion, thereby linking an altered electrophoretic mobility of the mutant protein to its abnormal function. Mutant huntingtin appeared in gray and white matter with no difference in expression in affected regions. The mutant protein was broader than the wild type and in 6 of 11 juvenile cases resolved as a complex of bands, consistent with evidence at the DNA level for somatic mosaicism. Thus, HD pathogenesis results from a gain of function by an aberrant protein that is widely expressed in brain and is harmful only to some neurons.
Assuntos
Encéfalo/metabolismo , Expressão Gênica , Doença de Huntington/genética , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Sequências Repetitivas de Ácido Nucleico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cerebelo/química , Córtex Cerebral/química , Feminino , Humanos , Proteína Huntingtina , Masculino , Pessoa de Meia-Idade , MosaicismoRESUMO
Mitochondrial defects including reduction of a key mitochondrial tricarboxylic acid cycle enzyme alpha-ketoglutarate-dehydrogenase complex (KGDHC) are characteristic of many neurodegenerative diseases. KGDHC consists of alpha-ketoglutarate dehydrogenase, dihydrolipoyl succinyltransferase (E2k), and dihydrolipoamide dehydrogenase (Dld) subunits. We investigated whether Dld or E2k deficiency influences adult brain neurogenesis using immunohistochemistry for the immature neuron markers, doublecortin (Dcx) and polysialic acid-neural cell adhesion molecule, as well as a marker for proliferation, proliferating cell nuclear antigen (PCNA). Both Dld- and E2k-deficient mice showed reduced Dcx-positive neuroblasts in the subgranular zone (SGZ) of the hippocampal dentate gyrus compared with wild-type mice. In the E2k knockout mice, increased immunoreactivity for the lipid peroxidation marker, malondialdehyde occurred in the SGZ. These alterations did not occur in the subventricular zone (SVZ). PCNA staining revealed decreased proliferation in the SGZ of E2k-deficient mice. In a transgenic mouse model of Alzheimer's disease, Dcx-positive cells in the SGZ were also reduced compared with wild type, but Dld deficiency did not exacerbate the reduction. In the malonate lesion model of Huntington's disease, Dld deficiency did not alter the lesion-induced increase and migration of Dcx-positive cells from the SVZ into the ipsilateral striatum. Thus, the KGDHC subunit deficiencies associated with elevated lipid peroxidation selectively reduced the number of neuroblasts and proliferating cells in the hippocampal neurogenic zone. However, these mitochondrial defects neither exacerbated certain pathological conditions, such as amyloid precursor protein (APP) mutation-induced reduction of SGZ neuroblasts, nor inhibited malonate-induced migration of SVZ neuroblasts. Our findings support the view that mitochondrial dysfunction can influence the number of neural progenitor cells in the hippocampus of adult mice.
Assuntos
Encéfalo/patologia , Proliferação de Células , Mitocôndrias/enzimologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/patologia , Neurônios/ultraestrutura , Aciltransferases/deficiência , Análise de Variância , Animais , Di-Hidrolipoamida Desidrogenase/deficiência , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Regulação Enzimológica da Expressão Gênica/genética , Peroxidação de Lipídeos/genética , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Doenças Neurodegenerativas/genética , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Coloração pela Prata/métodosRESUMO
Hypertension and tachycardia are well known features of acute porphyria and have been shown to be related to increased circulating catecholamines. The mechanism by which circulating catecholamines are increased was studied using the isolated perfused rat heart and human platelets as a model of adrenergic neuronal function. It was found that neither delta-aminolevulinate (ALA) nor porphobilinogen (PBG) blocked uptake or caused release in the isolated perfused rat heart. Platelets from six patients with acute prophyria, three in remission and three latent, with matching normal controls were studied with regard to their uptake of [(3)H]norepinephrine in the presence of ALA or PBG. It was found that ALA and PBG significantly reduced uptake and accumulation of [(3)H]-norepinephrine in patients with acute porphyria; however, no similar reduction in uptake and accumulation was observed in the platelets of normal controls. Therefore, it appears that there is a latent defect in the catecholamine uptake and (or) accumulation of platelets of patients with acute prophyria which only manifests itself in the presence of ALA or PBG. If platelet uptake serves as a model of adrenergic neuron uptake, this suggests that elevated circulating catecholamine levels during acute attacks of acute porphyria are caused at least partially by blockade of re-uptake into the sympathetic neurons.
Assuntos
Catecolaminas/metabolismo , Porfirias/metabolismo , Doença Aguda , Adolescente , Adulto , Ácido Aminolevulínico/farmacologia , Animais , Plaquetas/metabolismo , Catecolaminas/sangue , Eritrócitos/enzimologia , Feminino , Humanos , Hidroximetilbilano Sintase/sangue , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Norepinefrina/metabolismo , Porfobilinogênio/farmacologia , Porfirias/sangue , Cloreto de Potássio/farmacologia , RatosRESUMO
Mitochondria have been linked to both necrotic and apoptotic cell death, which are thought to have a major role in the pathogenesis of neurodegenerative diseases. Recent evidence shows that nuclear gene defects affecting mitochondrial function have a role in the pathogenesis of Friedreich's ataxia, Wilson's disease and hereditary spastic paraplegia. There is also accumulating evidence that mitochondrial dysfunction might have a role in the pathogenesis of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Alzheimer's disease. If this is so, a number of therapeutic targets are implicated that might result in novel treatments for neurodegenerative diseases.
Assuntos
Morte Celular/genética , DNA Mitocondrial/genética , Mitocôndrias/genética , Doenças Neurodegenerativas/genética , Animais , Humanos , Necrose , Doenças Neurodegenerativas/terapiaRESUMO
The pathogenesis of nerve cell death in neurodegenerative diseases is unknown. An attractive hypothesis is that an impairment of energy metabolism may underlie slow excitotoxic neuronal death. Several studies have demonstrated mitochondrial or oxidative defects in neurodegenerative diseases. Impaired energy metabolism results in decreases in high-energy phosphate stores and a deteriorating membrane potential. Under these conditions, the voltage-sensitive Mg2+ block of NMDA receptors is relieved, allowing the receptors to be persistently activated by endogenous concentrations of glutamate. In this way, metabolic defects may lead to neuronal death by a slow 'excitotoxic' mechanism. Recent studies indicate that such a mechanism occurs in vivo, and it may play a role in animal models of Huntington's disease and Parkinson's disease. If a similar mechanism occurs in neurodegenerative diseases in humans it may be possible to use either excitatory amino acid antagonists or agents to improve neuronal bioenergetics as therapeutic treatments for these disorders.
Assuntos
Metabolismo Energético , Mitocôndrias/metabolismo , Doenças do Sistema Nervoso/metabolismo , Encéfalo/efeitos dos fármacos , Humanos , Doenças do Sistema Nervoso/patologia , Neurotoxinas/farmacologiaRESUMO
An increasing body of evidence has implicated excitoxicity as a mechanism of neuronal death in both acute and chronic neurological diseases. A major recent advance has been the successful cloning and expression of the non-NMDA, NMDA, and metabotropic glutamate receptors. The cellular mechanisms responsible for cell death following activation of these receptors are still being clarified. A recent advance in conceptualizing excitotoxicity is the notion that a slow excitotoxic process may occur as a consequence of either a receptor abnormality or an impairment of energy metabolism. It is possible that such a mechanism may occur in neurodegenerative illnesses. Recent therapeutic studies have focused on glycine site antagonists and on the efficacy of non-NMDA antagonists in ischemia.
Assuntos
Aminoácidos/fisiologia , Doenças do Sistema Nervoso/fisiopatologia , Receptores de N-Metil-D-Aspartato/biossíntese , Animais , Clonagem Molecular , Humanos , Receptores de Aminoácido/fisiologiaRESUMO
A central role for defective mitochondrial energy production, and the resulting increased levels of free radicals, in the pathogenesis of various neurodegenerative diseases is gaining increasing acceptance. Defects in energy metabolism may contribute to both excitotoxicity and oxidative damage. Evidence implicating energy defects in neurodegenerative diseases comes from similarities to known mitochondrial disorders, including delayed and variable age of onset, slow progression, and symmetric degeneration of circumscribed groups of neurons.
Assuntos
Mitocôndrias/metabolismo , Encefalomiopatias Mitocondriais/metabolismo , Degeneração Neural , Estresse Oxidativo , Doença de Alzheimer/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Morte Celular , Metabolismo Energético , Radicais Livres , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Encefalomiopatias Mitocondriais/patologia , Encefalomiopatias Mitocondriais/fisiopatologia , Neurônios/patologiaAssuntos
Degeneração Neural/enzimologia , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Humanos , Intoxicação por MPTP/complicações , Intoxicação por MPTP/enzimologia , Camundongos , Camundongos Knockout , Degeneração Neural/etiologia , Degeneração Neural/genética , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase/deficiência , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Doença de Parkinson/enzimologia , Doença de Parkinson/etiologia , Doença de Parkinson/genéticaRESUMO
Huntington's disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder characterized by involuntary choreiform movements, cognitive decline and a progressive neuronal degeneration primarily affecting the striatum. There is at present no effective therapy against this disorder. The gene responsible for the disease (IT15) has been cloned and the molecular defect identified as an expanded polyglutamine tract in the N-terminal region of a protein of unknown function, named huntingtin (The Huntington's Disease Collaborative Research Group, 1993. Cell 72, 971-983). An intense, search for the cell pathology attached to this molecular defect is currently under way [see Sharp and Ross (1996, Neurobiol. Dis. 3, 3-15) for review]. Huntingtin interacts with a number of proteins, some of which have well identified functions, and it has thus been suggested that alterations in glycolysis, vesicle trafficking or apoptosis play a role in the physiopathology of HD. On the other hand data derived from positron emission tomography (PET), magnetic resonance spectroscopy and post-mortem biochemical evidence for a defect in succinate oxidation have suggested the implication of a primary impairment of mitochondrial energy metabolism. All these hypotheses are not necessarily to be opposed and recent findings indicate that the HD mutation could possibly directly alter mitochondrial functions which would in turn activate apoptotic pathways. To test this mitochondrial hypothesis, we studied the effects in rodents and non-human primates of a chronic blockade of succinate oxidation by systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP). Extensive behavioural and neuropathological evaluations showed that a partial but prolonged energy impairment induced by 3NP is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration at least partially by apoptosis. 3NP produces the preferential degeneration of the medium-sized spiny GABAergic neurons with a relative sparing of interneurons and afferents, as was observed in HD striatum. The present manuscript reviews the different aspects of this neurotoxic treatment in rodents and non-human primates, and its interest as a phenotypic model of HD to understand the degenerative process of HD and test new therapeutic strategies.
Assuntos
Modelos Animais de Doenças , Doença de Huntington/genética , Animais , Humanos , Doença de Huntington/fisiopatologia , FenótipoRESUMO
Alzheimer's Disease (AD) is characterized by cerebral accumulation of beta-amyloid peptides (Abeta), which are proteolytically derived from beta-amyloid precursor protein (betaAPP). betaAPP metabolism is highly regulated via various signal transduction systems, e.g., several serine/threonine kinases and phosphatases. Several growth factors known to act via receptor tyrosine kinases also have been demonstrated to regulate sbetaAPP secretion. Among these receptors, insulin and insulin-like growth factor-1 receptors are highly expressed in brain, especially in hippocampus and cortex. Emerging evidence indicates that insulin has important functions in brain regions involved in learning and memory. Here we present evidence that insulin significantly reduces intracellular accumulation of Abeta and that it does so by accelerating betaAPP/Abeta trafficking from the trans-Golgi network, a major cellular site for Abeta generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of Abeta both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on betaAPP metabolism is mediated via a receptor tyrosine kinase/mitogen-activated protein (MAP) kinase kinase pathway. The results suggest cell biological and signal transduction mechanisms by which insulin modulates betaAPP and Abeta trafficking in neuronal cultures.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Neurônios/metabolismo , Doença de Alzheimer/metabolismo , Animais , Membrana Celular/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Retículo Endoplasmático/metabolismo , Inibidores Enzimáticos/farmacologia , Espaço Extracelular/metabolismo , Complexo de Golgi/metabolismo , Insulina/farmacologia , Insulisina , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/fisiologia , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity are both associated with dopaminergic neuron death in the substantia nigra (SN). Apoptosis has been implicated in this cell loss; however, whether or not it is a major component of disease pathology remains controversial. Caspases are a major class of proteases involved in the apoptotic process. To evaluate the role of caspases in PD, we analyzed caspase activation in MPTP-treated mice, in cultured dopaminergic cells, and in postmortem PD brain tissue. MPTP was found to elicit not only the activation of the effector caspase-3 but also the initiators caspase-8 and caspase-9, mitochondrial cytochrome c release, and Bid cleavage in the SN of wild-type mice. These changes were attenuated in transgenic mice neuronally expressing the general caspase inhibitor protein baculoviral p35. These mice also displayed increased resistance to the cytotoxic effects of the drug. MPTP-associated toxicity in culture was found temporally to involve cytochrome c release, activation of caspase-9, caspase-3, and caspase-8, and Bid cleavage. Caspase-9 inhibition prevented the activation of both caspase-3 and caspase-8 and also inhibited Bid cleavage, but not cytochrome c release. Activated caspase-8 and caspase-9 were immunologically detectable within MPP(+)-treated mesencephalic dopaminergic neurons, dopaminergic nigral neurons from MPTP-treated mice, and autopsied Parkinsonian tissue from late-onset sporadic cases of the disease. These data demonstrate that MPTP-mediated activation of caspase-9 via cytochrome c release results in the activation of caspase-8 and Bid cleavage, which we speculate may be involved in the amplification of caspase-mediated dopaminergic cell death. These data suggest that caspase inhibitors constitute a plausible therapeutic for PD.