Axonal Integrity in the Absence of Functional Peroxisomes from Projection Neurons and Astrocytes
Axonal Integrity in the Absence of Functional Peroxisomes from Projection Neurons and Astrocytes
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DOI：
10.1002/glia.21027
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发表时间：
2010-10-01
期刊：
影响因子：
6.2
通讯作者：
Baes, Myriam
中科院分区：
文献类型：
--
作者：
Bottelbergs, Astrid;Verheijden, Simon;Baes, Myriam
在Nestin-Pex5基因敲除小鼠中，去除所有神经细胞的功能性过氧化体会导致显著的神经系统异常，包括运动和认知功能障碍，并伴有脱髓鞘、轴突变性和胶质增生。少突胶质细胞选择性CNP-Pex5基因敲除小鼠模型显示出类似的病理，但发病较晚，进展较慢。到目前为止，这些神经异常与已知的代谢变化之间的联系尚未确定，即极长链脂肪酸(VLCFA)的积累和血浆原的减少。我们现在关注的是过氧化物体在神经元和星形胶质细胞中的作用。神经元特异的过氧化体基因敲除模型NEX-Pex5既没有微观上的异常，也没有代谢上的异常，表明神经元内缺乏功能性的过氧化体并不会导致轴突损伤。当从GFAP-Pex5(-/-)小鼠的星形胶质细胞中删除过氧化物酶体时，轴突的完整性和正常行为也得到了保护。然而，过氧化体代谢产物在大脑中的调节失调，包括VLCFA的显著积累和血浆原的轻微减少。有趣的是，尽管GFAP-Pex5(-/-)小鼠的少突胶质细胞有少量靶向，但这些代谢扰动也存在于分离的髓鞘中，这表明过氧化体代谢物在不同类型的脑细胞之间穿梭。我们得出的结论是，神经元和星形胶质细胞中缺乏过氧化体代谢并不会引起从少突胶质细胞中去除过氧化体后观察到的神经退行性变表型。星形胶质细胞缺乏过氧化体代谢会导致髓鞘中VLCFA水平升高，但这对神经功能没有重大影响。(C)2010年Wiley-Liss。Inc.
Ablation of functional peroxisomes from all neural cells in Nestin-Pex5 knockout mice caused remarkable neurological abnormalities including motoric and cognitive malfunctioning accompanied by demyelination, axonal degeneration, and gliosis. An oligodendrocyte selective Cnp-Pex5 knockout mouse model shows a similar pathology, but with later onset and slower progression. Until now, the link between these neurological anomalies and the known metabolic alterations, namely the accumulation of very long-chain fatty acids (VLCFA) and reduction of plasmalogens, has not been established. We now focused on the role of peroxisomes in neurons and astrocytes. A neuron-specific peroxisome knockout model, NEX-Pex5, showed neither microscopic nor metabolic abnormalities indicating that the lack of functional peroxisomes within neurons does not cause axonal damage. Axonal integrity and normal behavior was also preserved when peroxisomes were deleted from astrocytes in GFAP-Pex5(-/-) mice. Nevertheless, peroxisomal metabolites were dysregulated in brain including a marked accumulation of VLCFA and a slight reduction in plasmalogens. Interestingly, despite minor targeting of oligodendrocytes in GFAP-Pex5(-/-) mice, these metabolic perturbations were also present in isolated myelin indicating that peroxisomal metabolites are shuttled between different brain cell types. We conclude that absence of peroxisomal metabolism in neurons and astrocytes does not provoke the neurodegenerative phenotype observed after deleting peroxisomes from oligodendrocytes. Lack of peroxisomal metabolism in astrocytes causes increased VLCFA levels in myelin, but this has no major impact on neurological functioning. (C) 2010 Wiley-Liss. Inc.