Pliss Lioudmila, Pentney Roberta J, Johnson Mark T, Patel Mulchand S
Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214, USA.
J Neurochem. 2004 Dec;91(5):1082-91. doi: 10.1111/j.1471-4159.2004.02790.x.
Pyruvate dehydrogenase complex (PDC) deficiency is an inborn metabolic disorder associated with a variety of neurologic abnormalities. This report describes the development and initial characterization of a novel murine model system in which PDC deficiency has been introduced specifically into the developing nervous system. The absence of liveborn male and a roughly 50% reduction in female offspring following induction of the X-linked mutation indicate that extensive deficiency of PDC in the nervous system leads to pre-natal lethality. Brain tissue from surviving females at post-natal days 15 and 35 was shown to have approximately 75% of wild-type PDC activity, suggesting that a threshold of enzyme activity exists for post-natal survival. Detailed histological analyses of brain tissue revealed structural defects such as disordered neuronal cytoarchitecture and neuropil fibers in grey matter, and reduced size of bundles and disorganization of fibers in white matter. Many of the histologic abnormalities resemble those found in human female patients who carry mutations in the X-linked ortholog. These findings demonstrate a requirement for PDC activity within the nervous system for survival in utero and suggest that impaired pyruvate metabolism in the developing brain can affect neuronal migration, axonal growth and cell-cell interactions.
丙酮酸脱氢酶复合体（PDC）缺乏症是一种与多种神经学异常相关的先天性代谢紊乱疾病。本报告描述了一种新型小鼠模型系统的建立及初步特征，该模型中PDC缺乏症已被特异性引入发育中的神经系统。诱导X连锁突变后，无存活雄性后代且雌性后代数量减少约50%，这表明神经系统中PDC的广泛缺乏会导致产前致死率。出生后第15天和第35天存活雌性小鼠的脑组织显示，其PDC活性约为野生型的75%，这表明存在产后存活的酶活性阈值。对脑组织的详细组织学分析揭示了结构缺陷，如灰质中神经元细胞结构和神经纤维紊乱，以及白质中束状结构变小和纤维紊乱。许多组织学异常与携带X连锁直系同源基因突变的人类女性患者中发现的异常相似。这些发现表明神经系统内的PDC活性是子宫内存活所必需的，并提示发育中大脑的丙酮酸代谢受损会影响神经元迁移、轴突生长和细胞间相互作用。
