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Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis

Department of Cellular Microbiology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 07/2010; 107(29):13046-50. DOI: 10.1073/pnas.1002396107
Source: PubMed

ABSTRACT ALS is a fatal motor neuron disease of adult onset. Neuroinflammation contributes to ALS disease progression; however, the inflammatory trigger remains unclear. We report that ALS-linked mutant superoxide dismutase 1 (SOD1) activates caspase-1 and IL-1beta in microglia. Cytoplasmic accumulation of mutant SOD1 was sensed by an ASC containing inflammasome and antagonized by autophagy, limiting caspase-1-mediated inflammation. Notably, mutant SOD1 induced IL-1beta correlated with amyloid-like misfolding and was independent of dismutase activity. Deficiency in caspase-1 or IL-1beta or treatment with recombinant IL-1 receptor antagonist (IL-1RA) extended the lifespan of G93A-SOD1 transgenic mice and attenuated inflammatory pathology. These findings identify microglial IL-1beta as a causative event of neuroinflammation and suggest IL-1 as a potential therapeutic target in ALS.

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Available from: Felix Meissner, Jan 23, 2014
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    • "Besides, affected astrocytes caused neuronal cell death when co-cultured, suggesting an important role of astrocytes in this disease (Meyer et al., 2014). Microglia have been shown to secrete IL-1β as a response to purified mutant SOD1 stimulation, which is thus an important pro-inflammatory trigger (Meissner et al., 2010). Also secretion of several other pro-inflammatory cytokines such as TFN-α, IFNγ, and IL-6 was reported, resulting in (more) activation of astrocytes and microglia (Evans et al., 2013). "
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    ABSTRACT: The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, and Huntington's disease, leading to the hypothesis that proteasomal impairment is contributing to these diseases. So far, most research related to the UPS in neurodegenerative diseases has been focused on neurons, while glial cells have been largely disregarded in this respect. However, glial cells are essential for proper neuronal function and adopt a reactive phenotype in neurodegenerative diseases, thereby contributing to an inflammatory response. This process is called reactive gliosis, which in turn affects UPS function in glial cells. In many neurodegenerative diseases, mostly neurons show accumulation and aggregation of ubiquitinated proteins, suggesting that glial cells may be better equipped to maintain proper protein homeostasis. During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins. Here we review the role of the UPS in glial cells in various neurodegenerative diseases, and we discuss how studying glial cell function might provide essential information in unraveling mechanisms of neurodegenerative diseases.
    Frontiers in Molecular Neuroscience 08/2014; 7:73. DOI:10.3389/fnmol.2014.00073
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    • "2A, C, D). Spinal cord tissue of ALS mice were shown to have elevated levels of secreted interferon-γ (IFNγ, Wang et al., 2011) and interleukin-1β (IL-1β, Meissner et al., 2010) during pre-symptomatic, symptomatic and end stages. Treatment of mixed motoneuron cultures or astrocyteenriched cultures with IFNγ and IL-1β resulted in an increase of Bid protein to levels comparable to those induced by LPS (Figs. 3C–F, Suppl. "
    Neurobiology of Disease 06/2014; · 5.20 Impact Factor
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    • "2A, C, D). Spinal cord tissue of ALS mice were shown to have elevated levels of secreted interferon-γ (IFNγ, Wang et al., 2011) and interleukin-1β (IL-1β, Meissner et al., 2010) during pre-symptomatic, symptomatic and end stages. Treatment of mixed motoneuron cultures or astrocyteenriched cultures with IFNγ and IL-1β resulted in an increase of Bid protein to levels comparable to those induced by LPS (Figs. 3C–F, Suppl. "
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    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.
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