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 hSOD1 G93A 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 (IP 3)-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP 3 can prompt IP 3 receptor (IP 3R)-mediated Ca 2+ release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca 2+ signaling that occurs downstream of mGluR5 in hSOD1 G93A-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca 2+ concentrations ([Ca 2+] i) in the absence of spontaneous oscillations. The interaction of IP 3Rs with the anti-apoptotic protein Bcl-X L was previously described to prevent cell death by modulating intracellular Ca 2+ signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-X L, fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca 2+ oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1 G93A 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. © The Author 2011. Published by Oxford University Press. All rights reserved

Martorana, F., Brambilla, L., Valori, C., Bergamaschi, C., Roncoroni, C., Aronica, E., et al. (2012). The BH4 domain of Bcl-X L rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals. HUMAN MOLECULAR GENETICS, 21(4), 826-840 [10.1093/hmg/ddr513].

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

Martorana, Francesca;
2012

Abstract

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 hSOD1 G93A 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 (IP 3)-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP 3 can prompt IP 3 receptor (IP 3R)-mediated Ca 2+ release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca 2+ signaling that occurs downstream of mGluR5 in hSOD1 G93A-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca 2+ concentrations ([Ca 2+] i) in the absence of spontaneous oscillations. The interaction of IP 3Rs with the anti-apoptotic protein Bcl-X L was previously described to prevent cell death by modulating intracellular Ca 2+ signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-X L, fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca 2+ oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1 G93A 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. © The Author 2011. Published by Oxford University Press. All rights reserved
Articolo in rivista - Articolo scientifico
Scientifica
Amyotrophic Lateral Sclerosis; Animals; Astrocytes; Cell Death; Female; Gene Expression Regulation; Humans; Male; Mice; Mice, Transgenic; Peptides; Protein Structure, Tertiary; Psychomotor Performance; Receptors, Kainic Acid; Superoxide Dismutase; Survival Analysis; bcl-X Protein; Calcium Signaling; Genetics; Genetics (clinical); Molecular Biology
English
Martorana, F., Brambilla, L., Valori, C., Bergamaschi, C., Roncoroni, C., Aronica, E., et al. (2012). The BH4 domain of Bcl-X L rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals. HUMAN MOLECULAR GENETICS, 21(4), 826-840 [10.1093/hmg/ddr513].
Martorana, F; Brambilla, L; Valori, C; Bergamaschi, C; Roncoroni, C; Aronica, E; Volterra, A; Bezzi, P; Rossi, D
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/105724
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