Sigma-1 receptor knockout increases α-synuclein aggregation and phosphorylation with loss of dopaminergic neurons in substantia nigra

摘要

Abstract Sigma-1 receptor (σ 1 R) is expressed in dopaminergic neurons of substantia nigra. Here, we show that σ 1 R knockout (σ 1 R ?/? ) 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 σ 1 R ?/? mice were age-dependently increased without the changes in αSyn monomers. The phosphorylation of αSyn monomers or oligomers in dopaminergic neurons was enhanced in σ 1 R ?/? mice. Levels of phosphorylated eIF2a and C/EBP homologous protein expression were elevated in σ 1 R ?/? 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 σ 1 R ?/? mice. Rifampicin reduced the late increase of αSyn oligomers in σ 1 R ?/? mice. Rifampicin or salubrinal could reduce the loss of dopaminergic neurons in σ 1 R ?/? mice and improved their motor coordination. The results indicate that the σ 1 R deficiency through enhanced aggregation and phosphorylation of αSyn causes the loss of dopaminergic neurons leading to the decline of motor coordination.