Bae Y-S, Yoon S H, Han J Y, Woo J, Cho Y S, Kwon S-K, Bae Y C, Kim D, Kim E, Kim M-H
Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, Korea.
Genes Brain Behav. 2018 Feb;17(2):126-138. doi: 10.1111/gbb.12419. Epub 2017 Sep 15.
Metabolic diseases affect various organs including the brain. Accumulation or depletion of substrates frequently leads to brain injury and dysfunction. Deficiency of aminopeptidase P1, a cytosolic proline-specific peptidase encoded by the Xpnpep1 gene, causes an inborn error of metabolism (IEM) characterized by peptiduria in humans. We previously reported that knockout of aminopeptidase P1 in mice causes neurodevelopmental disorders and peptiduria. However, little is known about the pathophysiological role of aminopeptidase P1 in the brain. Here, we show that loss of aminopeptidase P1 causes behavioral and neurological deficits in mice. Mice deficient in aminopeptidase P1 (Xpnpep1 ) display abnormally enhanced locomotor activities in both the home cage and open-field box. The aminopeptidase P1 deficiency in mice also resulted in severe impairments in novel-object recognition, the Morris water maze task, and contextual, but not cued, fear memory. These behavioral dysfunctions were accompanied by epileptiform electroencephalogram activity and neurodegeneration in the hippocampus. However, mice with a heterozygous mutation for aminopeptidase P1 (Xpnpep1 ) exhibited normal behaviors and brain structure. These results suggest that loss of aminopeptidase P1 leads to behavioral, cognitive and neurological deficits. This study may provide insight into new pathogenic mechanisms for brain dysfunction related to IEMs.
代谢性疾病会影响包括大脑在内的多个器官。底物的积累或消耗常常导致脑损伤和功能障碍。氨肽酶P1是一种由Xpnpep1基因编码的胞质脯氨酸特异性肽酶，其缺乏会导致一种以人类肽尿症为特征的先天性代谢缺陷（IEM）。我们之前报道过，小鼠体内氨肽酶P1的基因敲除会导致神经发育障碍和肽尿症。然而，关于氨肽酶P1在大脑中的病理生理作用却知之甚少。在此，我们表明氨肽酶P1的缺失会导致小鼠出现行为和神经功能缺陷。缺乏氨肽酶P1（Xpnpep1）的小鼠在饲养笼和旷场箱中均表现出异常增强的运动活动。小鼠体内氨肽酶P1的缺乏还导致在新物体识别、莫里斯水迷宫任务以及情境性（而非线索性）恐惧记忆方面出现严重障碍。这些行为功能障碍伴随着海马体中的癫痫样脑电图活动和神经退行性变。然而，氨肽酶P1杂合突变（Xpnpep1）的小鼠表现出正常的行为和脑结构。这些结果表明，氨肽酶P1的缺失会导致行为、认知和神经功能缺陷。这项研究可能为深入了解与IEMs相关的脑功能障碍的新致病机制提供线索。
