Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

Ghanashyam D. Ghadge, Barbara S. Slusher, Amos Bodner, Mauro Dal Canto, Krystyna Wozniak, Ajit G. Thomas, Camilo Rojas, Takashi Tsukamoto, Pavel Majer, Richard J. Miller, Anna Liza Monti, Raymond P. Roos

Research output: Contribution to journalArticlepeer-review

Abstract

Approximately 10% of cases of amyotrophic lateral sclerosis (ALS), a progressive and fatal degeneration that targets motor neurons (MNs), are inherited, and ≈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.

Original languageEnglish (US)
Pages (from-to)9554-9559
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number16
DOIs
StatePublished - Aug 5 2003
Externally publishedYes

ASJC Scopus subject areas

  • General

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