title: Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models.
abstract: Approximately 10% of cases of amyotrophic lateral sclerosis (ALS), a progressive and fatal degeneration that targets motor neurons (MNs), are inherited, and approximately 20% of these cases of familial ALS (FALS) are caused by mutations of copper/zinc superoxide dismutase type 1. Glutamate excitotoxicity has been implicated as a mechanism of MN death in both ALS and FALS. In this study, we tested whether a neuroprotective strategy involving potent and selective inhibitors of glutamate carboxypeptidase II (GCPII), which converts the abundant neuropeptide N-acetylaspartylglutamate to glutamate, could protect MNs in an in vitro and animal model of FALS. Data suggest that the GCPII inhibitors prevented MN cell death in both of these systems because of the resultant decrease in glutamate levels. GCPII inhibition may represent a new therapeutic target for the treatment of ALS.
authors.affiliation: Department of Neurology, University of Chicago School of Medicine, Chicago, IL 60637, USA.
authors.forename: Ghanashyam D
authors.initials: GD
authors.lastname: Ghadge
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Amos
authors.initials: A
authors.lastname: Bodner
authors.forename: Mauro Dal
authors.initials: MD
authors.lastname: Canto
authors.forename: Krystyna
authors.initials: K
authors.lastname: Wozniak
authors.forename: Ajit G
authors.initials: AG
authors.lastname: Thomas
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Pavel
authors.initials: P
authors.lastname: Majer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.forename: Anna Liza
authors.initials: AL
authors.lastname: Monti
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Roos
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D016923:Cell Death; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II