The peroxisome deficient PEX2 Zellweger mouse -: Pathologic and biochemical correlates of lipid dysfunction
The peroxisome deficient PEX2 Zellweger mouse -: Pathologic and biochemical correlates of lipid dysfunction
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DOI：
10.1385/jmn:16:2-3:289
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发表时间：
2001-04-01
影响因子：
3.1
通讯作者：
Moser, HW
中科院分区：
文献类型：
--
作者：
Faust, PL;Su, HM;Moser, HW
Zellweger综合征是一种典型的人类过氧化物酶体生物发生障碍，其导致中枢神经系统中的异常神经元迁移和严重的神经功能障碍。先前通过靶向缺失PEX 2过氧化物酶体基因开发了这种疾病的鼠模型。通过在体内用有丝分裂标记物标记神经元前体细胞，我们可以证明纯合PEX 2突变小鼠大脑皮质中神经元迁移的延迟。出生后的PEX 2 Zellweger小鼠出现严重的小脑缺陷，伴有浦肯野细胞发育异常和叶型改变。当将PEX 2突变置于近交系小鼠遗传背景上时，存在显著的胚胎致死性和遍及脑的广泛神经元变性。PEX 2突变小鼠的生化分析显示，在多种组织中存在超长链脂肪酸和缩醛磷脂缺乏的特征性蓄积。二十二碳六烯酸水平（DHA; 22：6 n-3）被发现在突变小鼠的大脑中减少，但出生时内脏器官正常。在出生后突变小鼠中检查的所有组织都具有减少的DHA。在这些小鼠的形态学和生化分析的结合使用将是必不可少的，以阐明这种复杂的过氧化物酶体疾病的发病机制。
Zellweger syndrome is the prototypic human peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. A murine model for this disorder was previously developed by targeted deletion of the PEX2 peroxisomal gene. By labeling neuronal precursor cells in vivo with a mitotic marker, we can demonstrate a delay in neuronal migration in the cerebral cortex of homozygous PEX2 mutant mice. Postnatal PEX2 Zellweger mice develop severe cerebellar defects with abnormal Purkinje cell development and an altered folial pattern. When the PEX2 mutation is placed on an inbred murine genetic background, there is significant embryonic lethality and widespread neuronal lipidosis throughout the brain. Biochemical analysis of PEX2 mutant mice shows the characteristic accumulation of very long chain fatty acids and deficient plasmalogens in a wide variety of tissues. Docosahexaenoic acid levels (DHA; 22:6 n-3) were found to be reduced in the brain of mutant mice but were normal in visceral organs at birth. All tissues examined in postnatal mutant mice had reduced DHA. The combined use of morphologic and biochemical analyses in these mice will be essential to elucidate the pathogenesis of this complex peroxisomal disease.