Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Madrid 28049, Spain.
Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Madrid 28049, Spain.
Mol Cell. 2017 May 4;66(3):358-372.e7. doi: 10.1016/j.molcel.2017.04.005.
A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1. Once in the nucleus, MGRN1 potentiates the transcriptional cellular response to proteotoxic stress. Inhibition of MGRN1 impairs ATF3-mediated neuronal responsiveness to proteosomal stress and increases neuronal stress, while increasing MGRN1 ameliorates signs of neuronal aging, including cognitive performance in old animals. Our results imply that, among others, the strength of neuronal survival in a proteasomal deterioration background, like during aging, depends on the fine-tuning of ubiquitination-deubiquitination.
蛋白酶体功能下降与神经元衰老和与衰老相关的神经病变有因果关系。通过在培养的海马神经元和体内实验，我们发现衰老会触发 E3 泛素连接酶 mahogunin（MGRN1）的减少和细胞质到细胞核的再分布。蛋白酶体功能障碍会诱导 MGRN1 的单泛素化，这是其核内进入的关键翻译后修饰。MGRN1 单泛素化的一个潜在机制是通过多泛素化的 MGRN1 在蛋白酶体上的逐步去泛素化。一旦进入细胞核，MGRN1 就能增强细胞对蛋白毒性应激的转录反应。抑制 MGRN1 会损害 ATF3 介导的神经元对蛋白酶体应激的反应能力，并增加神经元应激，而增加 MGRN1 则能改善神经元衰老的迹象，包括老年动物的认知表现。我们的结果表明，在蛋白酶体恶化背景下（如衰老期间），除其他因素外，神经元存活的强度取决于泛素化-去泛素化的精细调节。
