PEX11β deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function
PEX11β deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function
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DOI：
10.1128/mcb.22.12.4358-4365.2002
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发表时间：
2002-06-01
影响因子：
5.3
通讯作者：
Gould, SJ
中科院分区：
文献类型：
--
作者：
Li, XL;Baumgart, E;Gould, SJ
Zellweger综合征是一种致命的神经系统疾病，其特征是过氧化物酶体蛋白输入严重缺陷。由此产生的过氧化物酶体代谢缺陷和过氧化物酶体底物蓄积被认为是导致其他Zellweger综合征表型的原因，包括神经元迁移缺陷、张力减退、发育迟缓和新生儿致死。这些表型也表现在通过破坏PEX 5或PEX 2基因产生的Zellweger综合征小鼠模型中。在这里，我们发现，缺乏过氧化物酶体膜蛋白PEX 11 β的小鼠显示了Zellweger综合征小鼠模型共有的几个病理特征，包括神经元迁移缺陷，神经元凋亡增强，发育迟缓，张力减退和新生儿死亡。然而，PEX 11 β缺乏症与Zellweger综合征和Zellweger综合征小鼠的显著不同之处在于，它的特征不在于过氧化物酶体蛋白输入的可检测缺陷，并且仅显示过氧化物酶体脂肪酸β-氧化和过氧化物酶体醚脂质生物合成的轻度缺陷。这些结果表明，Zellweger综合征的神经病理学特征可以在没有过氧化物酶体酶错误定位的情况下发生，并挑战了目前Zellweger综合征发病机制的模型。
Zellweger syndrome is a lethal neurological disorder characterized by severe defects in peroxisomal protein import. The resulting defects in peroxisome metabolism and the accumulation of peroxisomal substrates are thought to cause the other Zellweger syndrome phenotypes, including neuronal migration defects, hypotonia, a developmental delay, and neonatal lethality. These phenotypes are also manifested in mouse models of Zellweger syndrome generated by disruption of the PEX5 or PEX2 gene. Here we show that mice lacking peroxisomal membrane protein PEX11beta display several pathologic features shared by these mouse models of Zellweger syndrome, including neuronal migration defects, enhanced neuronal apoptosis, a developmental delay, hypotonia, and neonatal lethality. However, PEX11beta deficiency differs significantly from Zellweger syndrome and Zellweger syndrome mice in that it is not characterized by a detectable defect in peroxisomal protein import and displays only mild defects in peroxisomal fatty acid beta-oxidation and peroxisomal ether lipid biosynthesis. These results demonstrate that the neurological pathologic features of Zellweger syndrome can occur without peroxisomal enzyme mislocalization and challenge current models of Zellweger syndrome pathogenesis.