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1.
Neurogenetics ; 13(1): 9-21, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22028146

RESUMO

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder and manifests at old age. While many details of its pathogenesis remain to be elucidated, in particular the protein and mitochondrial quality control during stress responses have been implicated in monogenic PD variants. Especially the mitochondrial kinase PINK1 and the ubiquitin ligase PARKIN are known to cooperate in autophagy after mitochondrial damage. As autophagy is also induced by loss of trophic signaling and PINK1 gene expression is modulated after deprivation of cytokines, we analyzed to what extent trophic signals and starvation stress regulate PINK1 and PARKIN expression. Time course experiments with serum deprivation and nutrient starvation of human SH-SY5Y neuroblastoma cells and primary mouse neurons demonstrated phasic induction of PINK1 transcript up to twofold and PARKIN transcript levels up to sixfold. The corresponding threefold starvation induction of PARKIN protein was limited by its translocation to lysosomes. Analysis of primary mouse cells from PINK1-knockout mice indicated that PARKIN induction and lysosomal translocation occurred independent of PINK1. Suppression of the PI3K-Akt-mTOR signaling by pharmacological agents modulated PARKIN expression accordingly. In conclusion, this expression survey demonstrates that PARKIN and PINK1 are coregulated during starvation and suggest a role of both PD genes in response to trophic signals and starvation stress.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Doença de Parkinson/fisiopatologia , Inanição , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular , Humanos , Lisossomos/metabolismo , Camundongos , Camundongos Knockout , Doença de Parkinson/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Ubiquitina-Proteína Ligases/genética
2.
Neurobiol Aging ; 30(10): 1574-86, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18295378

RESUMO

Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer's disease integrating genetic factors related to enhanced amyloid-beta (Ass) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. To further clarify the synergistic effects of aging and Ass pathology, we used isolated mitochondria of double Swedish and London mutant APP transgenic mice and of non-tg littermates. Pronounced mitochondrial dysfunction in adult Thy-1 APP mice, such as a drop of mitochondrial membrane potential and reduced ATP-levels already appeared at 3 months when elevated intracellular but not extracellular Ass deposits are present. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species, an altered Bcl-xL/Bax ratio and reduction of COX IV activity. We observed significant decreases in state 3 respiration and FCCP-uncoupled respiration in non-tg mice after treatment with extracellular Ass. Similar deficits were seen only in aged Thy-1 APP mice, probably due to compensation within the respiratory chain in young animals. We conclude that Ass dependent mitochondrial dysfunction starts already at 3 months in this AD model before extracellular deposition of Ass and progression accelerates substantially with aging.


Assuntos
Envelhecimento , Doença de Alzheimer/fisiopatologia , Mitocôndrias/fisiologia , Doenças Mitocondriais/fisiopatologia , Trifosfato de Adenosina/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Transporte de Elétrons/fisiologia , Feminino , Humanos , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estresse Oxidativo/fisiologia , Nexinas de Proteases , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
3.
Blood ; 97(12): 3941-50, 2001 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-11389038

RESUMO

It was previously shown that plasmin activates human peripheral monocytes in terms of lipid mediator release and chemotactic migration. Here it is demonstrated that plasmin induces proinflammatory cytokine release and tissue factor (TF) expression by monocytes. Plasmin 0.043 to 1.43 CTA U/mL, but not active site-blocked plasmin, triggered concentration-dependent expression of mRNA for interleukin-1alpha (IL-1alpha), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), and TF with maximum responses after 4 hours. Plasmin-mediated mRNA expression was inhibited in a concentration-dependent manner by the lysine analogue trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA). Increases in mRNA levels were followed by concentration- and time-dependent release of IL-1alpha, IL-1beta and TNF-alpha and by TF expression on monocyte surfaces. Neither cytokines nor TF could be detected when monocytes were preincubated with actinomycin D or cycloheximide. Electrophoretic mobility shift assays indicated plasmin-induced activation of NF-kappaB; DNA-binding complexes were composed of p50, p65, and c-Rel, as shown by supershift experiments. Nuclear translocation of NF-kappaB/Rel proteins coincided with IkappaBalpha degradation. At variance with endotoxic lipopolysaccharide, plasmin elicited the rapid degradation of another cytoplasmic NF-kappaB inhibitor, p105. Proteolysis of NF-kappaB inhibitors was apparently due to transient activation of IkappaB kinase (IKK) beta that reached maximum activity at 1 hour after plasmin stimulation. In addition, AP-1 binding was increased in plasmin-treated monocytes, with most complexes composed of JunD, c-Fos, and FosB. These findings further substantiate the role of plasmin as a proinflammatory activator of human monocytes and reveal an important new link between the plasminogen-plasmin system and inflammation. (Blood. 2001;97:3941-3950)


Assuntos
Citocinas/efeitos dos fármacos , Fibrinolisina/farmacologia , Monócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Tromboplastina/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Humanos , Quinase I-kappa B , Inflamação/metabolismo , Cinética , Monócitos/metabolismo , NF-kappa B/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/farmacologia , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tromboplastina/genética , Tromboplastina/metabolismo , Fator de Transcrição AP-1/farmacologia , Regulação para Cima/efeitos dos fármacos
4.
Arch Virol ; 144(5): 921-33, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10416375

RESUMO

The unique region of mRNA 5 of murine hepatitis virus contains two open reading frames, ORF 5a and ORF 5b. The downstream ORF 5b encodes the envelope (E) protein, an integral membrane protein of the virus. We have shown previously that the expression of ORF 5b is mediated by the internal entry of ribosomes. In the experiments reported here, we have used the in vitro translation of synthetic mRNAs to identify the region of mRNA 5 that mediates internal ribosome entry. Our results show that the 5' border of the MHV mRNA 5 IRES element is located between nucleotides 227 and 244 in ORF 5a, while the 3' border is located between nucleotides 140 and 172 in ORF 5b. The MHV mRNA 5 IRES element, therefore, contains not more than 280 nucleotides and encompasses the ORF 5b initiation codon. As evidenced by electrophoretic mobility shift assays, the IRES element of mRNA 5 interacts specifically with protein factors present in an L-cell lysate.


Assuntos
Vírus da Hepatite Murina/genética , Fases de Leitura Aberta , RNA Mensageiro/genética , RNA Viral/genética , Ribossomos/virologia , Animais , Sequência de Bases , Sistema Livre de Células , Primers do DNA , Células L , Camundongos , Dados de Sequência Molecular , Vírus da Hepatite Murina/fisiologia , Plasmídeos , Reação em Cadeia da Polimerase , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica
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