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

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