The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes.
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.
Science Foundation Ireland (08/INV.1/B1949), Health Research Board (RP/2007/283) and Higher Education Authority Program for Research in Third Level Institutions (PRTLI) Cycle 5, BIO-AT Ph.D. Scholarship.
CommentsThis is the author’s version of a work that was accepted for publication in Neurobiology of Disease. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neurobiology of Disease. 2014 pii: S0969-9961(14)00172-7 . DOI: 10.1016/j.nbd.2014.06.008 It is available at http://www.journals.elsevier.com/neurobiology-of-disease/
Published CitationKoenig HG, Coughlan KS, Kinsella S, Breen BA, Prehn JHM. The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes. Neurobiology of Disease. 2014 pii: S0969-9961(14)00172-7 [Epub ahead of print]
- Physiology and Medical Physics