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1.
Acta Myol ; 30(1): 4-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21842586

RESUMO

Neuroinflammation is a pathological hallmark of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), and is characterized by activated microglia at sites of neuronal injury. In ALS, neurons do not die alone; neuronal injury is noncell-autonomous and depends upon a well-orchestrated dialogue between motor neurons and microglia. Evidence from transgenic models expressing mutant superoxide dismutase 1 (SOD) suggests that the dialogue between motor neurons and microglia initially protects motor neurons. However, with increasing stress and injury within motor neurons, induced by the presence of misfolded proteins such as mSOD1, mitochondrial function and axoplasmic flow are impaired and endoplasmic reticulum stress is induced; misfolded proteins themselves or alternate signals are released from motor neurons and activate microglia. Activated microglia, in turn, switch from anti-inflammatory and neuroprotective to proinflammatory and neurotoxic. Neurotoxic signaling from motor neurons promotes microglial release of reactive oxygen species and pro-inflammatory cytokines further enhancing motor neuron stress and cell injury and initiating a self-propagating cycle of motor neuron injury and cell death. A greater understanding of how to restore the imbalance between neuroprotection and cytotoxicity will depend upon a greater understanding of the motor neuron-microglial dialogue.


Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Microglia/fisiologia , Neurônios Motores/fisiologia , Animais , Comunicação Celular , Morte Celular , Retículo Endoplasmático/fisiologia , Humanos , Mediadores da Inflamação/metabolismo , Mitocôndrias Musculares/fisiologia , Dobramento de Proteína , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxido Dismutase/fisiologia , Superóxido Dismutase-1
3.
Neurology ; 71(17): 1326-34, 2008 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-18936424

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS), an inexorably progressive motoneuron disease, is accompanied by significantly increased markers of inflammation. These inflammatory constituents could protect, harm, do neither, or do both. OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in patients with sporadic ALS to suppress neuroinflammation and improve clinical outcomes after CNS engraftment. METHODS: Six patients with definite ALS received total body irradiation followed by peripheral blood HSCT infusion from human leukocyte antigen identically matched sibling donors. Disease progression and survival were assessed monthly and compared with matched historic database patients. Autopsy samples from brain and spinal cord were examined immunohistochemically and by quantitative reverse-transcriptase polymerase chain reaction. Donor-derived DNA in brain and spinal cord tissue was evaluated for the extent of chimerism. RESULTS: No clinical benefits were evident. Four patients were 100% engrafted; postmortem tissue examination in two of the 100% engrafted patients demonstrated 16% to 38% donor-derived DNA at sites with motoneuron pathology, which may correspond to the observed increased CD68 or CD1a-positive cells. Neither donor DNA nor increased cell numbers were found in several unaffected brain regions. A third minimally engrafted patient had neither donor DNA nor increased infiltrating cells in the CNS. CONCLUSIONS: This study demonstrates that peripheral cells derived from donor hematopoietic stem cells can enter the human CNS primarily at sites of motoneuron pathology and engraft as immunomodulatory cells. Although unmodified hematopoietic stem cells did not benefit these sporadic amyotrophic lateral sclerosis patients, such cells may provide a cellular vehicle for future CNS gene therapy.


Assuntos
Esclerose Lateral Amiotrófica/cirurgia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adulto , Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos
4.
Neurology ; 62(9): 1611-2, 2004 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-15136693

RESUMO

The presence of oxidative damage and increased iron deposition in CNS tissues of ALS patients prompted the authors to examine the prevalence of two common HFE gene mutations linked to iron accumulation and consequent oxidative stress. The prevalence of the C282Y and H63D mutations was nearly identical in 51 ALS patients and 47 normal control subjects. The presence of either mutation did not significantly affect the age at onset or rate of progression in ALS.


Assuntos
Esclerose Lateral Amiotrófica/genética , Hemocromatose/genética , Mutação , Esclerose Lateral Amiotrófica/diagnóstico , Cromossomos Humanos Par 6/genética , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Hemocromatose/diagnóstico , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estresse Oxidativo/genética , Fatores de Risco
5.
Neurology ; 62(10): 1758-65, 2004 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-15159474

RESUMO

BACKGROUND: Markers of oxidative stress and immune activation are significantly elevated in postmortem ALS CNS tissue, although the relevance to pathogenesis is unclear. OBJECTIVE: To determine the degree and distribution of oxidative stress and immune activation in living ALS patients and whether these levels correlate with the rate of progression or extent of disease. METHOD: Serum and CSF samples from sporadic ALS (sALS) patients were assayed for 4-hydroxy-2,3-nonenal (HNE), a lipid peroxidation product, and monocyte chemoattractant protein-1alpha (MCP-1alpha), a beta-chemokine, by high-performance liquid chromatography and ELISA and compared with levels measured in disease and normal control subjects by one-way analysis of variance. SALS serum levels were analyzed in relation to rate of progression, stage of disease, and drug therapy. RESULTS: HNE levels were significantly elevated in the sera and spinal fluid of sALS patients compared with control populations and positively correlated with extent of disease but not rate of progression. MCP-1alpha levels were also elevated in the sera of sALS patients, with the exception of the neurodegenerative disease control subjects, but decreased with advancing disease. CSF MCP-1alpha levels were not different between the sampled populations. There was no correlation between serum HNE and MCP-1alpha levels in sALS patients and extent of disease. However, an inverse relationship between HNE and MCP-1alpha was demonstrable in vitro. Low levels of HNE stimulated release of MCP-1alpha from cultured human macrophages, whereas high levels inhibited release of MCP-1alpha. CONCLUSIONS: These data confirm the presence of increased oxidative stress and immune activation in ALS patients. HNE is also suggested as a possible biomarker of disease.


Assuntos
Aldeídos/sangue , Esclerose Lateral Amiotrófica/sangue , Quimiocina CCL2/sangue , Peroxidação de Lipídeos , Adulto , Idoso , Aldeídos/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/imunologia , Biomarcadores , Quimiocina CCL2/metabolismo , Progressão da Doença , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano , Estresse Oxidativo
6.
Neurology ; 62(2): 319-22, 2004 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-14745081

RESUMO

Expression of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) is a known response to oxidative damage of DNA. In ALS brain, PARP expression by western analyses was increased in the motor cortex, parietal cortex, and cerebellum. PARP immunostaining in the motor cortex was increased in ALS neurons and subcortical glia and macrophages. Importantly, there was widespread increased PARP expression in neurons in the parietal cortex and cerebellum, regions that are typically clinically unaffected in ALS, suggesting widespread oxidative stress.


Assuntos
Esclerose Lateral Amiotrófica/enzimologia , Encéfalo/enzimologia , Proteínas do Tecido Nervoso/análise , Poli(ADP-Ribose) Polimerases/análise , Biomarcadores , Cerebelo/enzimologia , Indução Enzimática , Humanos , Macrófagos/enzimologia , Pessoa de Meia-Idade , Córtex Motor/enzimologia , Neuroglia/enzimologia , Neurônios/enzimologia , Estresse Oxidativo , Lobo Parietal/enzimologia
7.
Mol Cell ; 7(5): 1095-101, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11389855

RESUMO

The p21-activated kinase, Shk1, is essential for viability, establishment and maintenance of cell polarity, and proper mating response in the fission yeast, Schizosaccharomyces pombe. Here we describe the characterization of a highly conserved, WD repeat protein, Skb15, which negatively regulates Shk1 in fission yeast. A null mutation in the skb15 gene is lethal and results in deregulation of actin polymerization and localization, microtubule biogenesis, and the cytokinetic machinery, as well as a substantial uncoupling of these processes from the cell cycle. Loss of Skb15 function is suppressed by partial loss of Shk1, demonstrating that negative regulation of Shk1 by Skb15 is required for proper execution of cytoskeletal remodeling and cytokinetic functions. A mouse homolog of Skb15 can substitute for its counterpart in fission yeast, demonstrating that Skb15 protein function has been substantially conserved through evolution.


Assuntos
Proteínas Fúngicas/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces/química , Actinas/efeitos dos fármacos , Animais , Sequência Conservada , Citoesqueleto/efeitos dos fármacos , Evolução Molecular , Proteínas Fúngicas/genética , Camundongos , Microtúbulos/efeitos dos fármacos , Mutação , Quinases Ativadas por p21
8.
Virus Res ; 50(1): 95-106, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9255939

RESUMO

We have analyzed the activity of a specific portion of the latency-associated transcript (LAT) promoter of three strains of herpes simplex virus type 1 (HSV-1) in neuronal and non-neuronal cell types. Restriction fragments containing the LAT promoter sequences and the 5'-end of the LATs were isolated from HSV-1 strains H129, +GC and KOS-63, sequenced and cloned into a chloramphenicol transferase (CAT) plasmid vector. These vectors were separately assayed for CAT production in human (SknSH) and mouse (C-1300) neuroblastoma cell lines and a human continuous cell line (HeLa). Strain KOS-63 contained a C to T base substitution within the LAT promoter binding factor element upstream of the cAMP response element binding sequence. In replicate experiments, in which the construct DNA was used for transfection, the CAT constructs from strains H129 and +GC functioned equally well in all three cell lines. In contrast, the strain KOS-63 CAT construct functioned significantly better in HeLa cells than in neuroblastoma cell lines and better than the identical CAT constructs from strains H129 and +GC. In addition, the construct from strain KOS-63 functioned less well in the human neuroblastoma cell line than in HeLa or C-1300 neuroblastoma cells. When LAT expression was examined directly in vivo by in situ hybridization, strain KOS-63 produced slightly less LAT RNA than strain H129 within trigeminal ganglionic neurons of latently infected rabbits. However, utilizing competitive gel-shift assays, DNA fragments containing the LAT promoter binding element from all three strains bound equivalent amounts of HeLa cell nuclear proteins. Together, these results suggest that the activity expressed by the strain KOS-63 LAT promoter in vivo and in vitro may relate to positive or negative effects of DNA binding proteins on LAT transcription, and that these effects are cell-type dependent.


Assuntos
Herpesvirus Humano 1/genética , Regiões Promotoras Genéticas , Transcrição Gênica , Latência Viral/genética , Animais , Sequência de Bases , Células HeLa , Humanos , Camundongos , Dados de Sequência Molecular , Neuroblastoma , Coelhos , Gânglio Trigeminal/virologia , Células Tumorais Cultivadas
9.
J Neurol Sci ; 131(2): 119-27, 1995 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7595636

RESUMO

Survivors of herpes simplex encephalitis (HSE) experience intellectual impairment and an inability to store and recall information. Because the temporal lobes and associated limbic structures are central to storage and retrieval of memories, and are predominantly affected in adult HSE, injury to these areas is postulated to cause behavioral and learning disabilities. A previous study (Beers et al., 1993) demonstrated that intranasal inoculation of Lewis rats with herpes simplex virus type-1 (HSV-1) induced acute partial complex seizures, and hemorrhagic and inflammatory lesions of the hippocampus and entorhinal cortex. Consequently, it was of interest to determine whether rats that had recovered from HSE had limbic system-associated memory impairments. Therefore, rats were evaluated when signs and symptoms of encephalitis were no longer apparent using an eight arm radial maze to assess the acquisition and retention of learned information. An allocentric-spatial location paradigm revealed HSV-1 infected rats performed at chance levels on both acquisition and retention which were statistically different from sham-inoculated controls. However, using an egocentric-spatial left/right discrimination task, infected rats performed statistically similar to sham-inoculated controls. Furthermore, HSV-1 nucleic acids were detected in the nuclei of neurons within the hippocampus and entorhinal cortex using in situ hybridization techniques. Of interest was the observation that rats with learning and memory deficits had no apparent histopathological or immunocytochemical evidence of antecedent CNS infection. This is the first experimental demonstration that HSV-1 can cause behavioral impairments in the absence of obvious inflammatory injury to the temporal lobe memory system.


Assuntos
Sistema Nervoso Central/virologia , Encefalite Viral/psicologia , Herpes Simples , Memória/fisiologia , Comportamento Espacial/fisiologia , Animais , Astrócitos/virologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiologia , Feminino , Proteína Glial Fibrilar Ácida/análise , Hibridização In Situ , Sistema Límbico/química , Sistema Límbico/fisiopatologia , Sistema Límbico/virologia , Ratos , Ratos Endogâmicos Lew , Lobo Temporal/química , Lobo Temporal/fisiopatologia , Lobo Temporal/virologia
10.
Arch Virol ; 140(9): 1663-75, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-7487498

RESUMO

EcoRI fragments of herpes simplex virus I (HSV-1) strains H129 and +GC were cloned and the EcoRI and BglII restriction enzyme sites were mapped. Comparison of these enzyme sites with the sequence of HSV-1 strain 17syn+ demonstrated that all EcoRI sites were identical. For H129, the BglII sites were also found to match strain 17syn+ BglII sites. With one exception, the BglII sites in strain +GC also aligned with the strain 17syn+ sequence. The one exception was a missing BglII site from strain +GC located between bases 25,149 and 25,154 in the EcoRI D fragment within the viral deoxyribonuclease gene (UL12). The BglII site represents the first difference to be mapped within HSV-1 strains H129 and +GC which have unique pathobiological properties in animal models of acute and reactivated infections.


Assuntos
Herpesvirus Humano 1/genética , Clonagem Molecular , DNA Viral/genética , Mapeamento por Restrição , Especificidade da Espécie
11.
J Neuropathol Exp Neurol ; 52(3): 241-52, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-8388040

RESUMO

Herpes simplex virus type 1 (HSV-1) is the cause of a serious and often fatal encephalitis. Patients who survive herpes simplex encephalitis (HSE) experience behavioral abnormalities including profound cognitive dysfunctions. We have developed a rat model of acute HSE to investigate the cognitive impairments caused by HSV-1 central nervous system (CNS) infection. Following intranasal inoculation of Lewis rats with a neurovirulent strain of HSV-1, animals shed virus in both ocular and nasal secretions and developed clinical signs of infection, including partial complex motor seizures that eventually generalized. Homogenization assays demonstrated infectious virus in the trigeminal ganglia, olfactory bulbs, and the piriform and entorhinal cortices. Histopathological assessment revealed inflammatory and hemorrhagic lesions in the trigeminal ganglia, olfactory bulbs, amygdala, hippocampus, the piriform and entorhinal cortices, and the spinal trigeminal nuclei. Viral antigens and nucleic acids were also detected within these structures by immunofluorescence microscopy and in situ hybridization, respectively. Viral-induced astrocytic hypertrophy in the CNS was demonstrated by glial fibrillary acidic protein immunoreactivity. Together, these results indicate that HSV-1 has the ability to invade, replicate, and induce site-specific CNS damage in the Lewis rat.


Assuntos
Encefalite/microbiologia , Ratos Endogâmicos Lew/microbiologia , Simplexvirus , Animais , Antígenos Virais/análise , Córtex Cerebral/microbiologia , DNA Viral/análise , Modelos Animais de Doenças , Encefalite/genética , Encefalite/imunologia , Encefalite/patologia , Feminino , Hibridização In Situ , Bulbo Olfatório/microbiologia , RNA Viral/análise , Ratos , Simplexvirus/genética , Simplexvirus/imunologia , Simplexvirus/isolamento & purificação , Gânglio Trigeminal/microbiologia
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