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

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.