全身敲除或兴奋神经元条件敲除L2A／LAMP2a的表达
首先，作者在小鼠中进行全身敲除或兴奋神经元条件敲除L2A/LAMP2a的表达。两种小鼠均出现了行为症状，全身敲除和条件敲除的小鼠症状类似。在到达六月龄时，兴奋神经元条件敲除小鼠出现脂褐质和K63泛素化蛋白累积，进一步提示蛋白降解清除出现了问题。 进一步，作者对小鼠的不可溶组份蛋白进行了数量蛋白组学分析，表明在L2A敲除小鼠中聚集了大量不可溶蛋白，其中75%蛋白含有KFERQ亚基。平时易聚集的蛋白，如alpha-syn，tau等，在CMA被抑制后，出现了过饱和状态向不可溶组份迁移。下一步，作者比较了分子伴侣自噬（L2A）和巨自噬（ATG7）分别抑制后的不可溶蛋白组份（下图）。分子伴侣自噬和巨自噬影响了不同途径的蛋白系列。例如CMA阻断后，物质内吞减少，网格蛋白聚集而AP2网格蛋白受体则减少；微丝蛋白动态调控相关蛋白也出现了聚集。 在分子伴侣自噬被抑制后，蛋白降解出现异常，神经元功能受到了影响。作者猜测在神经退行性疾病中，C......阅读全文
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