Hong Juan, Wang Ling, Zhang Tingting, Zhang Baofeng, Chen Ling
State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China; Department of Physiology, Nanjing Medical University, Nanjing, China.
Department of Physiology, Nanjing Medical University, Nanjing, China.
Neurobiol Aging. 2017 Nov;59:171-183. doi: 10.1016/j.neurobiolaging.2017.08.007. Epub 2017 Aug 10.
Sigma-1 receptor (σR) is expressed in dopaminergic neurons of substantia nigra. Here, we show that σR knockout (σR) mice, at age 6-12 months, appeared with age-related loss of dopaminergic neurons and decline of motor coordination. Levels of α-synuclein (αSyn) oligomers and fibrillar αSyn in substantia nigra of σR mice were age-dependently increased without the changes in αSyn monomers. The phosphorylation of αSyn monomers or oligomers in dopaminergic neurons was enhanced in σR mice. Levels of phosphorylated eIF2a and C/EBP homologous protein expression were elevated in σR mice with decline of proteasome activity. Inhibition of endoplasmic reticulum stress by salubrinal recovered the αSyn phosphorylation and proteasome activity and prevented early oligomerization of αSyn in σR mice. Rifampicin reduced the late increase of αSyn oligomers in σR mice. Rifampicin or salubrinal could reduce the loss of dopaminergic neurons in σR mice and improved their motor coordination. The results indicate that the σR deficiency through enhanced aggregation and phosphorylation of αSyn causes the loss of dopaminergic neurons leading to the decline of motor coordination.
西格玛-1受体（σR）在黑质的多巴胺能神经元中表达。在此，我们表明，6至12个月大的σR基因敲除（σR）小鼠出现了与年龄相关的多巴胺能神经元丧失和运动协调性下降。σR小鼠黑质中α-突触核蛋白（αSyn）寡聚体和纤维状αSyn的水平随年龄依赖性增加，而αSyn单体水平无变化。σR小鼠多巴胺能神经元中αSyn单体或寡聚体的磷酸化增强。σR小鼠中磷酸化eIF2a和C/EBP同源蛋白表达水平升高，同时蛋白酶体活性下降。用沙芦比诺抑制内质网应激可恢复σR小鼠中αSyn的磷酸化和蛋白酶体活性，并防止αSyn早期寡聚化。利福平可减少σR小鼠中αSyn寡聚体后期的增加。利福平或沙芦比诺可减少σR小鼠中多巴胺能神经元的丧失并改善其运动协调性。结果表明，σR缺乏通过增强αSyn的聚集和磷酸化导致多巴胺能神经元丧失，进而导致运动协调性下降。
