The proapoptotic BCL-2 family member BIM mediates motoneuron loss in a model of amyotrophic lateral sclerosis

University of Santiago, Chile, CiudadSantiago, Santiago Metropolitan, Chile
Cell Death and Differentiation (Impact Factor: 8.18). 08/2007; 14(7):1386-9. DOI: 10.1038/sj.cdd.4402166
Source: PubMed

Full-text preview

Available from:
  • Source
    • "BH3-only proteins responsible for the activation of Bax (and potentially Bak) in animal models of ALS were also recently identified . The BH3-only protein Bim was shown to be transcriptionally up-regulated in response to mtSOD1 overexpression, and deletion of bim protected against motoneuron loss in mtSOD1 mice in vivo (Hetz et al., 2007). We showed recently that endoplasmic reticulum stress was able to activate the BH3-only protein Puma in motoneurons , and that deletion of puma protected motoneurons against cell death in vitro and in mtSOD1 mice (Kieran et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons in the spinal cord, brainstem and motor cortex. Mutations in the superoxide dismutase 1 (SOD1) gene represent a frequent genetic determinant and recapitulate a disease phenotype similar to ALS when expressed in mice. Previous studies using SOD1(G93A) transgenic mice have suggested a paracrine mechanism of neuronal loss, in which cytokines and other toxic factors released from astroglia or microglia trigger motoneuron degeneration. Several pro-inflammatory cytokines activate death receptors and may downstream from this activate the Bcl-2 family protein, Bid. We here sought to investigate the role of Bid in astrocyte activation and non-cell autonomous motoneuron degeneration. We found that spinal cord Bid protein levels increased significantly during disease progression in SOD1(G93A) mice. Subsequent experiments in vitro indicated that Bid was expressed at relatively low levels in motoneurons, but was enriched in astrocytes and microglia. Bid was strongly induced in astrocytes in response to pro-inflammatory cytokines or exposure to lipopolysaccharide. Experiments in bid-deficient astrocytes or astrocytes treated with a small molecule Bid inhibitor demonstrated that Bid was required for the efficient activation of transcription factor nuclear factor-κB in response to these pro-inflammatory stimuli. Finally, we found that conditioned medium from wild-type astrocytes, but not from bid-deficient astrocytes, was toxic when applied to primary motoneuron cultures. Collectively, our data demonstrate a new role for the Bcl-2 family protein Bid as a mediator of astrocyte activation during neuroinflammation, and suggest that Bid activation may contribute to non-cell autonomous motoneuron degeneration in ALS.
    Full-text · Article · Jun 2014 · Neurobiology of Disease
  • Source
    • "Overexpressing Bcl-2 delays caspase activation in the mutant SOD1 G93A transgenic animal (Vukosavic et al., 2000) and silencing Bim protein expression delays disease onset in other animal models of the disease. A similar anti-apoptotic effect is seen in cell culture models of mutant SOD1 ALS (Hetz et al., 2007; Soo et al., 2012). In mutant SOD1 G85R -expressing Neuro2a cells, Bim deletion leads to reduced Bax recruitment to mitochondria and decreased cytochrome c redistribution. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective death of upper and lower motor neurons which ultimately leads to paralysis and ultimately death. Pathological changes in ALS are closely associated with pronounced and progressive changes in mitochondrial morphology, bioenergetics and calcium homeostasis. Converging evidence suggests that impaired mitochondrial function could be pivotal in the rapid neurodegeneration of this condition. In this review, we provide an update of recent advances in understanding mitochondrial biology in the pathogenesis of ALS and highlight the therapeutic value of pharmacologically targeting mitochondrial biology to slow disease progression.Linked ArticlesThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit
    Full-text · Article · Apr 2014 · British Journal of Pharmacology
  • Source
    • "In contrast, we showed that XBP1 deficiency protects against the development of ALS [26]. Similarly, targeting ASK1, a downstream signaling component of IRE1 [29], or ablating the expression of BIM or PUMA delays ALS [30], [31]. These studies illustrate the complex nature of the UPR, where the functional impact of the pathway to ALS may actually depend on the specific outputs regulated by particular UPR signaling modules [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Full-text · Article · Jul 2013 · PLoS ONE
Show more