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 ≈20% of these cases of familial ALS (FALS) are caused by mutations of copper/zinc superoxide dismutase type 1. Glutamate excitotoxicity has bee...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 100; no. 16; pp. 9554 - 9559
Main Authors Ghadge, Ghanashyam D., Slusher, Barbara S., Bodner, Amos, Canto, Mauro Dal, Wozniak, Krystyna, Thomas, Ajit G., Rojas, Camilo, Tsukamoto, Takashi, Majer, Pavel, Miller, Richard J., Monti, Anna Liza, Roos, Raymond P.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 05.08.2003
National Acad Sciences
Subjects
Adenoviridae - genetics
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - enzymology
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Animal models
Animals
Biological Sciences
Carboxypeptidases - antagonists & inhibitors
Cell Death
Cell Survival
Cellular biology
Enzyme Inhibitors - pharmacology
Enzymes
Glutamate Carboxypeptidase II
Glutamic Acid - metabolism
Mice
Mice, Transgenic
Motor neurons
Motor Neurons - metabolism
N methyl D aspartate receptors
Neurons
Neurons - enzymology
Neurons - pathology
Neuroscience
Spinal cord
Time Factors
Transgenic animals
Vehicles
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 23
ObjectType-Article-1
ObjectType-Feature-2
Deceased February 28, 2003.
To whom correspondence should be addressed at: Department of Neurology/MC2030, University of Chicago School of Medicine, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail: rroos@neurology.bsd.uchicago.edu.
This paper was submitted directly (Track II) to the PNAS office.
Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD
Abbreviations: ALS, amyotrophic lateral sclerosis; CXQA, 6-cyano-7-nitroquinoxaline-2,3-dione; EGLU, (2S)-α-ethylglutamic acid; FALS, familial ALS; MNs, motor neurons; MT, mutant; SOD1, copper/zinc superoxide dismutase type 1; NMDA, N-methyl-d-aspartate; GCPII, glutamate carboxypeptidase II; NAAG, N-acetylaspartylglutamate; mGluR; metabotropic glutamate receptor; mGluR3, mGluR subtype 3; TGFβ, transforming growth factor β; 2-PMPA, 2-(phosphonomethyl)pentanedioic acid; AdV, adenovirus; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; MK801, (+)-MK801 hydrogen maleate; 2-MPPA, 2-(3-mercaptopropyl)pentanedioic acid.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1530168100