The cellular response to a decrease in protein degradation by 26S proteasomes in chronic diseases is poorly understood. Pharmacological inhibition of proteasomes increases the expression of proteasome subunits and Proteasome Activator 200 (PA200), an alternative proteasome activator. In the S63del mouse model of the peripheral neuropathy Charcot Marie Tooth 1B (CMT1B), proteasomal protein degradation is decreased and proteasome gene expression is increased. Here, we show an increase in PA200 and PA200-bound proteasomes in the peripheral nerves of S63del mice. To test genetically whether the upregulation of PA200 was compensatory, we generated S63del//PA200-/- mice. Unexpectedly, in the sciatic nerves of these mice, there was greater proteasomal protein degradation than in S63del, less polyubiquitinated proteins and markers of the unfolded protein response, and a greater amount of assembled, active 26S proteasomes. These changes were not seen in PA200-/- controls and were therefore specific to the neuropathy. Furthermore, in S63del//PA200-/- mice, myelin thickness and nerve conduction were restored to WT levels. Thus, the upregulation of PA200 is maladaptive in S63del mice and its genetic ablation prevented neuropathy.

中文翻译：

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PA200 的敲除可改善蛋白毒性神经病中的蛋白酶体降解和髓鞘形成。

在慢性疾病中，细胞对 26S 蛋白酶体蛋白质降解减少的反应知之甚少。蛋白酶体的药理抑制会增加蛋白酶体亚基和蛋白酶体激活剂 200 (PA200)（另一种蛋白酶体激活剂）的表达。在周围神经病 Charcot Marie Tooth 1B (CMT1B) 的 S63del 小鼠模型中，蛋白酶体蛋白降解减少，蛋白酶体基因表达增加。在这里，我们展示了 S63del 小鼠周围神经中 PA200 和 PA200 结合蛋白酶体的增加。为了从基因角度测试 PA200 的上调是否是补偿性的，我们生成了 S63del//PA200-/- 小鼠。出乎意料的是，在这些小鼠的坐骨神经中，蛋白酶体蛋白降解程度比 S63del 更大，多泛素化蛋白和未折叠蛋白反应标记物更少，而组装的活性 26S 蛋白酶体数量更多。这些变化在 PA200-/- 对照中未见，因此是神经病变所特有的。此外，在S63del//PA200-/-小鼠中，髓磷脂厚度和神经传导恢复至WT水平。因此，PA200 的上调在 S63del 小鼠中是适应不良的，其基因消除可以预防神经病变。