Titre
The BH4 domain of Bcl-X(L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Martorana, F.
Auteure/Auteur
Brambilla, L.
Auteure/Auteur
Valori, C.F.
Auteure/Auteur
Bergamaschi, C.
Auteure/Auteur
Roncoroni, C.
Auteure/Auteur
Aronica, E.
Auteure/Auteur
Volterra, A.
Auteure/Auteur
Bezzi, P.
Auteure/Auteur
Rossi, D.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1460-2083
Statut éditorial
Publié
Date de publication
2012
Volume
21
Numéro
4
Première page
826
Dernière page/numéro d’article
840
Peer-reviewed
Oui
Langue
anglais
Résumé
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.
PID Serval
serval:BIB_BC2304B49CD9
PMID
Open Access
Oui
Date de création
2012-01-27T06:42:02.473Z
Date de création dans IRIS
2025-05-21T04:54:27Z
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Nom
REF.pdf
Version du manuscrit
published
Taille
589.53 KB
Format
Adobe PDF
PID Serval
serval:BIB_BC2304B49CD9.P001
URN
urn:nbn:ch:serval-BIB_BC2304B49CD92
Somme de contrôle
(MD5):63409b8ea88bf6c0f404eb6352c0e672