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The BH4 domain of Bcl-XL rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals

Martorana, Francesca ; Brambilla, Liliana ; Valori, Chiara F. ; Bergamaschi, Chiara ; Roncoroni, Chiara ; Aronica, Eleonora ; Volterra, Andrea ; Bezzi, Paola ; Rossi, Daniela

In: Human Molecular Genetics, 2012, vol. 21, no. 4, p. 826-840

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    Titel
    • The BH4 domain of Bcl-XL rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals
    Autor
    • Martorana, Francesca. Laboratory for Research on Neurodegenerative Disorders, IRCCS Fondazione Salvatore Maugeri, 27100 Pavia, Italy
    • Brambilla, Liliana. Laboratory for Research on Neurodegenerative Disorders, IRCCS Fondazione Salvatore Maugeri, 27100 Pavia, Italy
    • Valori, Chiara F.. Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy
    • Bergamaschi, Chiara. Laboratory for Research on Neurodegenerative Disorders, IRCCS Fondazione Salvatore Maugeri, 27100 Pavia, Italy
    • Roncoroni, Chiara. Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy
    • Aronica, Eleonora. Department of Neuropathology, Academisch Medisch Centrum, 1105 AZ Amsterdam, The Netherlands and
    • Volterra, Andrea. Department of Cell Biology and Morphology, University of Lausanne, 1005 Lausanne, Switzerland
    • Bezzi, Paola. Department of Cell Biology and Morphology, University of Lausanne, 1005 Lausanne, Switzerland
    • Rossi, Daniela. Laboratory for Research on Neurodegenerative Disorders, IRCCS Fondazione Salvatore Maugeri, 27100 Pavia, Italy
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Human Molecular Genetics, 2012, vol. 21, no. 4, p. 826-840. Oxford University Press
    Andere elektronische Ausgabe
    Klassifikation
    • Gesundheit
    OAI-PMH-ID
    • oai:doc.rero.ch:295088
    Summary
    Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1G93A mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP3)-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP3 can prompt IP3 receptor (IP3R)-mediated Ca2+ release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca2+ signaling that occurs downstream of mGluR5 in hSOD1G93A-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca2+ concentrations ([Ca2+]i) in the absence of spontaneous oscillations. The interaction of IP3Rs with the anti-apoptotic protein Bcl-XL was previously described to prevent cell death by modulating intracellular Ca2+ signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-XL, fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca2+ oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1G93A mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays the onset of the disease and improves both motor performance and animal lifespan. Our results point at TAT-BH4 as a novel glioprotective agent with a therapeutic potential for ALS