Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation
Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation
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DOI：
10.1093/brain/awf043
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发表时间：
2002-03-01
期刊：
影响因子：
14.5
通讯作者：
Griffiths, IR
中科院分区：
文献类型：
--
作者：
Garbern, JY;Yool, DA;Griffiths, IR
轴突变性导致获得性脱髓鞘疾病多发性硬化症的临床残疾。轴突变性发生在与炎症相关的急性发作期间，以及在炎症不明显的疾病的慢性进展期。为了探索中枢神经系统少突胶质细胞和轴突之间相互作用的重要性，我们分析了编码中枢神经系统髓鞘蛋白-蛋白脂蛋白(PLP1，以前的PLP)基因零突变的啮齿动物和人类的大脑。对Plp1缺失小鼠的中枢神经系统和PLP1缺失突变患者的尸检材料进行组织学分析，以评估轴突和髓鞘的完整性。对PLP1缺失者进行活体质子磁共振波谱(MRS)检测轴突完整性标志物N-乙酰天冬氨酸(NAA)水平。在Plp1基因缺失小鼠的中枢神经系统中发现了无脱髓鞘的长度依赖性轴突变性。PLP1缺陷患者的质子磁共振波谱显示NAA水平降低，这与轴突丢失一致。对患者脑组织的分析也显示了轴突丢失的长度依赖模式，但没有明显的脱髓鞘。因此，缺乏主要髓鞘蛋白PLP1的人和小鼠都会发生轴突变性。这种变性是长度依赖的，类似于遗传性脱髓鞘神经病患者的PNS中发现的，但与显著的脱髓鞘无关。因此，PLP1介导的轴突-神经胶质细胞相互作用的中断可能导致这种轴突变性。类似的机制可能导致多发性硬化症患者的轴突变性和临床残疾。
Axonal degeneration contributes to clinical disability in the acquired demyelinating disease multiple sclerosis. Axonal degeneration occurs during acute attacks, associated with inflammation, and during the chronic progressive phase of the disease in which inflammation is not prominent. To explore the importance of interactions between oligodendrocytes and axons in the CNS, we analysed the brains of rodents and humans with a null mutation in the gene encoding the major CNS myelin protein, proteolipid protein (PLP1, previously PLP). Histological analyses of the CNS of Plp1 null mice and of autopsy material from patients with null PLP1 mutations were performed to evaluate axonal and myelin integrity. In vivo proton magnetic resonance spectroscopy (MRS) of PLP1 null patients was conducted to measure levels of N-acetyl aspartate (NAA), a marker of axonal integrity. Length-dependent axonal degeneration without demyelination was identified in the CNS of Plp1 null mice. Proton MRS of PLP1-deficient patients showed reduced NAA levels, consistent with axonal loss. Analysis of patients' brain tissue also demonstrated a length-dependent pattern of axonal loss without significant demyelination. Therefore, axonal degeneration occurs in humans as well as mice lacking the major myelin protein PLP1. This degeneration is length-dependent, similar to that found in the PNS of patients with the inherited demyelinating neuropathy, CMT1A, but is not associated with significant demyelination. Disruption of PLP1-mediated axonal-glial interactions thus probably causes this axonal degeneration. A similar mechanism may be responsible for axonal degeneration and clinical disability that occur in patients with multiple sclerosis.