title: The BH4 domain of Bcl-X(L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals.
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(3)R)-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(3)Rs 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.
authors.affiliation: Laboratory for Research on Neurodegenerative Disorders, IRCCS Fondazione Salvatore Maugeri, 27100 Pavia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Martorana
authors.forename: Liliana
authors.initials: L
authors.lastname: Brambilla
authors.forename: Chiara F
authors.initials: CF
authors.lastname: Valori
authors.forename: Chiara
authors.initials: C
authors.lastname: Bergamaschi
authors.forename: Chiara
authors.initials: C
authors.lastname: Roncoroni
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Andrea
authors.initials: A
authors.lastname: Volterra
authors.forename: Paola
authors.initials: P
authors.lastname: Bezzi
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011597:Psychomotor Performance / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis; D051020:bcl-X Protein / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D010455:Peptides; D018092:Kainic Acid Receptors; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D051020:bcl-X Protein; C000606290:SOD1 protein, human; C540574:TAT-BH4 peptide; C000606291:Sod1 protein, mouse