期刊
FASEB JOURNAL
卷 25, 期 10, 页码 3674-3686出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-182337
关键词
astrocytes; neurodegenerative disease; splice variants; white matter
资金
- National Fund for Scientific Research (Belgium, Conventions des Fonds de la Recherche Scientifique Medicale) [3.4560.07, 1.5.109.09.F]
- DIANE research program of Belgium's Walloon region
- Queen Elisabeth Medical Foundation
- Association Belge pour les Maladies Neuromusculaires
Degeneration of corpus callosum appears in patients with amyotrophic lateral sclerosis (ALS) before clinical signs of upper motor neuron death. Considering the ALS-associated impairment of astrocytic glutamate uptake, we have characterized the expression and activity of the glutamate transporter isoforms GLT-1a and GLT-1b in the corpus callosum of transgenic rats expressing a mutated form of the human superoxide dismutase 1 (hSOD1(G93A)). We have also studied the effect of peptide histidine isoleucine (PHI), a vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 2 (VPAC(2)) agonist on glutamate transporters both in vivo and in callosal astrocytes. Before the onset of motor symptoms, the expression of both transporter isoforms was correlated with a constitutive activity of caspase-3. This enzyme participates in the down-regulation of GLT-1 in ALS, and here we demonstrated its involvement in the selective degradation of GLT-1a in the white matter. A single stereotactic injection of PHI into the corpus callosum of symptomatic rats decreased caspase-3 activity and promoted GLT-1a expression and uptake activity. Together, with evidence for a reduced expression of prepro-VIP/PHI mRNA in the corpus callosum of transgenic animals, these data shed light on the modulatory role of the VIP/PHI system on the glutamatergic transmission in ALS.-Goursaud, S., Focant, M. C., Berger, J. V., Nizet, Y., Maloteaux, J.-M., Hermans, E. The VPAC(2) agonist peptide histidine isoleucine (PHI) up-regulates glutamate transport in the corpus callosum of a rat model of amyotrophic lateral sclerosis (hSOD1(G93A)) by inhibiting caspase-3 mediated inactivation of GLT-1a. FASEB J. 25, 3674-3686 (2011). www.fasebj.org
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