| First Author | Hong J | Year | 2017 |
| Journal | Neurobiol Aging | Volume | 59 |
| Pages | 171-183 | PubMed ID | 28870519 |
| Mgi Jnum | J:249735 | Mgi Id | MGI:6093196 |
| Doi | 10.1016/j.neurobiolaging.2017.08.007 | Citation | Hong J, et al. (2017) Sigma-1 receptor knockout increases alpha-synuclein aggregation and phosphorylation with loss of dopaminergic neurons in substantia nigra. Neurobiol Aging 59:171-183 |
| abstractText | Sigma-1 receptor (sigma1R) is expressed in dopaminergic neurons of substantia nigra. Here, we show that sigma1R knockout (sigma1R(-/-)) mice, at age 6-12 months, appeared with age-related loss of dopaminergic neurons and decline of motor coordination. Levels of alpha-synuclein (alphaSyn) oligomers and fibrillar alphaSyn in substantia nigra of sigma1R(-/-) mice were age-dependently increased without the changes in alphaSyn monomers. The phosphorylation of alphaSyn monomers or oligomers in dopaminergic neurons was enhanced in sigma1R(-/-) mice. Levels of phosphorylated eIF2a and C/EBP homologous protein expression were elevated in sigma1R(-/-) mice with decline of proteasome activity. Inhibition of endoplasmic reticulum stress by salubrinal recovered the alphaSyn phosphorylation and proteasome activity and prevented early oligomerization of alphaSyn in sigma1R(-/-) mice. Rifampicin reduced the late increase of alphaSyn oligomers in sigma1R(-/-) mice. Rifampicin or salubrinal could reduce the loss of dopaminergic neurons in sigma1R(-/-) mice and improved their motor coordination. The results indicate that the sigma1R deficiency through enhanced aggregation and phosphorylation of alphaSyn causes the loss of dopaminergic neurons leading to the decline of motor coordination. |
