Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models.
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.
Ghadge
Ghanashyam D
GD
Department of Neurology, University of Chicago School of Medicine, Chicago, IL 60637, USA.
Slusher
Barbara S
BS
Bodner
Amos
A
Canto
Mauro Dal
MD
Wozniak
Krystyna
K
Thomas
Ajit G
AG
Rojas
Camilo
C
Tsukamoto
Takashi
T
Majer
Pavel
P
Miller
Richard J
RJ
Monti
Anna Liza
AL
Roos
Raymond P
RP
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
D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II