Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London SE5 9NU, UK.
Hum Mol Genet. 2009 Nov 1;18(21):4066-80. doi: 10.1093/hmg/ddp355. Epub 2009 Jul 29.
Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1(-/-) model of infantile NCL and Cln6(nclf) model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as in vivo biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.
神经元蜡样质脂褐质沉积症（NCLs；Batten 病）是儿童最常见的常染色体隐性神经退行性疾病，但潜在的细胞和分子机制仍不清楚。有几条证据表明，神经元的非体细胞区室（轴突和突触）在引发和进展 NCL 发病机制方面发挥着重要作用。在这里，我们报告了两种不同的 NCL 小鼠模型的轴突和突触的进行性破坏：婴儿期 NCL 的 Ppt1(-/-)模型和变异晚婴期 NCL 的 Cln6(nclf)模型。这些小鼠的丘脑和皮层中出现了突触病变，但在丘脑内发生得更早。对以前与调节轴突和突触脆弱性相关的一组蛋白质的表达水平进行定量比较，发现 NCL 小鼠的两种品系中涉及突触功能/稳定性和细胞周期调节的蛋白质发生了变化。蛋白质表达的变化发生在预/早期症状阶段，早于形态学可检测到的突触或轴突病变，并且再次表现出区域选择性，首先发生在丘脑内，仅在皮层中后来发生。尽管所研究的两种 NCL 模型之间存在个体蛋白质表达谱的显著差异，但在这两种模型的预/早期症状时间点，15 种研究蛋白中的 2 种（VDAC1 和 Pttg1）显示出明显的变化。我们的研究表明，突触和轴突是 NCL 中的重要早期病变靶点，并确定了 VDAC1 和 Pttg1 这两种蛋白，它们有可能作为 NCL 中预/早期轴突和突触脆弱性的体内生物标志物。
