Persistence of psychosine in brain lipid rafts is a limiting factor in the therapeutic recovery of a mouse model for Krabbe disease.
Persistence of psychosine in brain lipid rafts is a limiting factor in the therapeutic recovery of a mouse model for Krabbe disease.
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DOI：
10.1002/jnr.22564
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发表时间：
2011-03
影响因子：
4.2
通讯作者：
Bongarzonel, E. R.
中科院分区：
文献类型：
--
作者：
White, A. B.;Galbiati, F.;Givogri, M. I.;Rosas, A. Lopez;Qiu, X.;van Breemen, R.;Bongarzonel, E. R.
关键词：
鞘磷脂是膜脂筏的固有成分。这些分子的异常积聚可能导致这些区域的结构和功能改变，导致细胞功能障碍。半乳糖鞘氨醇是一种致病性脂代谢相关分子，在难治性脑白质营养不良Krabbe病(KD)中积聚可导致脑恶化和不可逆的神经功能障碍。在KD的治疗中，清除脂筏中过量的致病性精神病素的相关性还没有被调查。本文介绍的工作表明，精神病素抑制RAFT介导的神经细胞内吞作用。此外，尽管体外酶重组足以逆转受影响神经细胞中相关的内源性缺陷，但在KD小鼠模型中，传统的体内酶疗法似乎不足以完全消除RAFT相关的精神肽的致病水平。这项工作描述了一种机制，可能有助于限制传统疗法治疗KD的体内疗效。
Sphingolipids are intrinsic components of membrane lipid rafts. The abnormal accumulation of these molecules may introduce architectural and functional changes in these domains, leading to cellular dysfunction. Galactosylsphingosine (psychosine) is a pathogenic lipid-raft associated molecule whose accumulation leads to brain deterioration and irreversible neurological handicap in the incurable leukodystrophy Krabbe disease (KD). The relevance of clearing excessive levels of pathogenic psychosine from lipid rafts in therapy for KD has not been investigated. The work presented here demonstrates that psychosine inhibits raft-mediated endocytosis in neural cells. In addition, while in vitro enzyme reconstitution is sufficient for the reversal of related endocytic defects in affected neural cells, traditional in vivo enzyme therapies in the mouse model of KD appear insufficient for complete removal of pathogenic levels of raft-associated psychosine. This work describes a mechanism that may contribute to limit the in vivo efficacy of traditional therapies for KD.
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