Psychosine Accumulates in Membrane Microdomains in the Brain of Krabbe Patients, Disrupting the Raft Architecture
Psychosine Accumulates in Membrane Microdomains in the Brain of Krabbe Patients, Disrupting the Raft Architecture
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DOI：
10.1523/jneurosci.5597-08.2009
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发表时间：
2009-05-13
影响因子：
5.3
通讯作者：
Bongarzone, Ernesto R.
中科院分区：
文献类型：
--
作者：
White, Adam B.;Givogri, Maria I.;Bongarzone, Ernesto R.
脂筏（LRs）是以高浓度胆固醇和鞘脂为特征的膜领域。通常，它们被描绘成支架，许多不同的信号分子可以在其上组装级联反应。筏作为支架的想法正在获得显着的关注，因为LR中断的后果已被证明是在多个信号通路中表现出来的。在这项研究中，LRs在抽搐（TWI）小鼠，一个真正的模型，婴儿变异的人类球状细胞脑白质营养不良或克拉伯病，脑进行了调查。该小鼠具有GALC（β-半乳糖神经酰胺酶）活性缺陷，导致一些半乳糖鞘脂在脑中进行性积累。我们假设，Psychosine（半乳糖基鞘氨醇）在TWI CNS中的积累可能导致不同细胞群（如神经元和少突胶质细胞，疾病期间的细胞靶点）中筏的破坏。在这次交流中，我们证明了精神病特异性地积累在TWI大脑和坐骨神经以及人类Krabbe患者大脑样本中的LRs中。它还表明，这种积累是伴随着在这些领域的胆固醇的增加和LR标志物flotillin-2和小窝蛋白-1的分布的变化。最后，我们证明了这种现象可能提供了一种机制，通过这种机制，精神病碱可以发挥其已知的抑制蛋白激酶C的作用。这项研究提供了一个以前未描述的生物物理方面的发病机制在克拉伯病。
Lipid rafts (LRs) are membrane realms characterized by high concentrations of cholesterol and sphingolipids. Often, they are portrayed as scaffolds on which many different signaling molecules can assemble their cascades. The idea of rafts as scaffolds is garnering significant attention as the consequences of LR disruption have been shown to be manifest in multiple signaling pathways. In this study, LRs in the brain of the twitcher (TWI) mouse, a bona-fide model for infant variants of human globoid cell leukodystrophy or Krabbe disease, were investigated. This mouse has deficient activity of GALC (beta-galactosylceramidase) that leads to a progressive accumulation of some galactosyl-sphingolipids in the brain. We hypothesized that the accumulation of psychosine (galactosyl-sphingosine) in the TWI CNS may result in the disruption of rafts in different cell populations such as neurons and oligodendrocytes, both cellular targets during disease. In this communication, we demonstrate that psychosine specifically accumulates in LRs in the TWI brain and sciatic nerve and in samples from brains of human Krabbe patients. It is also shown that this accumulation is accompanied by an increase in cholesterol in these domains and changes in the distribution of the LR markers flotillin-2 and caveolin-1. Finally, we show evidence that this phenomenon may provide a mechanism by which psychosine can exert its known inhibitory effect on protein kinase C. This study provides a previously undescribed biophysical aspect for the mechanism of pathogenesis in Krabbe disease.