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1.
PLoS One ; 8(7): e66672, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23874395

RESUMO

Endoplasmic reticulum (ER) stress represents an early pathological event in amyotrophic lateral sclerosis (ALS). ATF4 is a key ER stress transcription factor that plays a role in both adaptation to stress and the activation of apoptosis. Here we investigated the contribution of ATF4 to ALS. ATF4 deficiency reduced the rate of birth of SOD1(G86R) transgenic mice. The fraction of ATF4(-/-)-SOD1(G85R) transgenic mice that were born are more resistant to develop ALS, leading to delayed disease onset and prolonged life span. ATF4 deficiency completely attenuated the induction of pro-apoptotic genes, including BIM and CHOP, and also led to quantitative changes in the ER protein homeostasis network. Unexpectedly, ATF4 deficiency enhanced mutant SOD1 aggregation at the end stage of the disease. Studies in the motoneuron cell line NSC34 demonstrated that knocking down ATF4 enhances mutant SOD1 aggregation possibly due to alteration in the redox status of the cell. Our results support a functional role of ATF4 in ALS, offering a novel target for disease intervention.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Esclerose Lateral Amiotrófica/fisiopatologia , Estresse do Retículo Endoplasmático/fisiologia , Regulação da Expressão Gênica/genética , Fator 4 Ativador da Transcrição/deficiência , Animais , Western Blotting , Linhagem Celular , Primers do DNA/genética , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Mutação de Sentido Incorreto/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/genética , Superóxido Dismutase-1
2.
Cell Death Dis ; 3: e272, 2012 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-22337234

RESUMO

Spinal cord injury (SCI) is a major cause of paralysis, and involves multiple cellular and tissular responses including demyelination, inflammation, cell death and axonal degeneration. Recent evidence suggests that perturbation on the homeostasis of the endoplasmic reticulum (ER) is observed in different SCI models; however, the functional contribution of this pathway to this pathology is not known. Here we demonstrate that SCI triggers a fast ER stress reaction (1-3 h) involving the upregulation of key components of the unfolded protein response (UPR), a process that propagates through the spinal cord. Ablation of X-box-binding protein 1 (XBP1) or activating transcription factor 4 (ATF4) expression, two major UPR transcription factors, leads to a reduced locomotor recovery after experimental SCI. The effects of UPR inactivation were associated with a significant increase in the number of damaged axons and reduced amount of oligodendrocytes surrounding the injury zone. In addition, altered microglial activation and pro-inflammatory cytokine expression were observed in ATF4 deficient mice after SCI. Local expression of active XBP1 into the spinal cord using adeno-associated viruses enhanced locomotor recovery after SCI, and was associated with an increased number of oligodendrocytes. Altogether, our results demonstrate a functional role of the UPR in SCI, offering novel therapeutic targets to treat this invalidating condition.


Assuntos
Fator 4 Ativador da Transcrição/genética , Proteínas de Ligação a DNA/genética , Traumatismos da Medula Espinal/genética , Medula Espinal/metabolismo , Fatores de Transcrição/genética , Ativação Transcricional/genética , Resposta a Proteínas não Dobradas/genética , Fator 4 Ativador da Transcrição/deficiência , Animais , Axônios/patologia , Contagem de Células , Proteínas de Ligação a DNA/deficiência , Dependovirus , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Vetores Genéticos , Injeções Espinhais , Locomoção , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oligodendroglia/patologia , Fatores de Transcrição de Fator Regulador X , Transdução de Sinais/genética , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Fatores de Transcrição/deficiência , Proteína 1 de Ligação a X-Box
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