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
Department of Neurology, University of Chicago School of Medicine, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9554-9. doi: 10.1073/pnas.1530168100. Epub 2003 Jul 22.
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.
肌萎缩侧索硬化症（ALS）是一种进行性致命性疾病，主要侵袭运动神经元（MNs），约10%的病例为遗传性，其中约20%的家族性ALS（FALS）病例由铜/锌超氧化物歧化酶1型突变引起。谷氨酸兴奋性毒性被认为是ALS和FALS中MN死亡的一种机制。在本研究中，我们测试了一种神经保护策略，该策略涉及谷氨酸羧肽酶II（GCPII）的强效和选择性抑制剂，GCPII可将丰富的神经肽N-乙酰天冬氨酰谷氨酸转化为谷氨酸，在FALS的体外和动物模型中该策略是否能保护MNs。数据表明，由于谷氨酸水平的降低，GCPII抑制剂在这两个系统中均能防止MN细胞死亡。抑制GCPII可能代表了治疗ALS的一个新的治疗靶点。
