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  • Serine phosphorylation is thought to be one of

    2020-07-27

    Serine 129 phosphorylation is thought to be one of the most important posttranslational modifications of αSyn. One of the principal observations in this study is that the phosphorylation (S129) of αSyn was observably potentiated in 6- and 9-month-old σ1R−/− mice. The level of phosphor-αSyn in dopaminergic neurons was observably increased in 6-month-old σ1R−/− mice. The levels of αSyn monomer (S-Fig. 2A) and oligomers (S-Fig. 2B) in 12-month-old σ1R−/− mice showed a tendency to decrease in comparison with 9-month-old σ1R−/− mice, but the level of αSyn oligomers was higher than that in 12-month-old WT mice. A possible reason might be the mass loss of dopaminergic neurons in 12-month-old WT mice. The level of phosphor-αSyn had no significant difference between 9- and 12-month-old σ1R−/− mice. The αSyn phosphorylation can induce the activation of ER stress (Sugeno et al., 2008). The levels of phosphorylated eIF2a and the CHOP protein were elevated in the SN of 6- and 9-month-old σ1R−/− mice. The increased αSyn phosphorylation in 6- and 9-month-old σ1R−/− mice could be corrected by the ER stress inhibitor. The increasing σ1R activation can counteract the ER stress (Hayashi and Su, 2007). The activation of σ1R is known to clear out neuronal nuclear inclusions via ER-associated protein degradation (Miki et al., 2014). In addition, the activation of σ1R serves as an adaptive response to clear misfolded proteins (Menendez-Benito et al., 2005). The excess of misfolded protein leads to the inhibition of proteasome function. Proteasome activity is lower in rna polymerase transfected with σ1R siRNA (Miki et al., 2015). The decline of proteasome activity in the SN of σ1R−/− mice was rescued by the ER stress inhibitor. Proteasomal inhibition can increase the phosphorylation (S129) of αSyn (Chau et al., 2009). Thus, it is highly likely that the σ1R deficiency via the induction of ER stress depresses the proteasome activity to enhance the αSyn phosphorylation (Fig. 7). The phosphorylation of αSyn monomers was increased in σ1R−/− mice, and the treatment with rifampicin had no effects on the increased phosphor-αSyn in σ1R−/− mice. The findings indicate that the enhanced phosphorylation of αSyn in σ1R−/− mice is not as a result of the αSyn aggregation. Another critical finding in this study is that the level of αSyn oligomers in the SN of σ1R−/− mice was progressively increased with age, whereas the levels of αSyn monomers and αSyn messenger RNA (data not shown) were not altered compared to WT mice. A number of studies reported that soluble αSyn monomers are degraded by the 26S proteasome (Tofaris et al., 2001). Dysfunction or knockdown of σ1R can directly impair proteasomal degradation pathways with 20S proteasome (Prause et al., 2013). Thus, it is proposed that the decline of proteasome activity in σ1R−/− mice may affect the clearance of αSyn monomers. The αSyn fibril content and the fibril formation of αSyn in dopaminergic neurons showed an age-related increase in σ1R−/− mice. The overexpression of σ1R can decrease the levels of GM1 and GM2 in lipid rafts (Takebayashi et al., 2004). The asialo-GM1 has an affinity for αSyn through the negative charge on the head group and the sugars, leading to the accumulation of αSyn and a weak inhibition of αSyn fibrillation (Martinez et al., 2007). An increase of GM2 is associated with the accumulation of αSyn in the patients with Sandhoff disease, a lysosomal storage disease (Suzuki et al., 2003). The application of rifampicin can prevent the β-sheet aggregates of αSyn (Lin et al., 2017). Rifampicin can inhibit αSyn fibrillation and disaggregate existing fibrils through stabilized αSyn as a monomer and soluble oligomers (Li et al., 2004). Aging has been associated with an increase in αSyn oligomers (Chen et al., 2016). The administration of rifampicin attenuated the level of αSyn oligomer in 9-month-old σ1R−/− mice. Thus, it is conceivable that the σ1R deficiency increases age-dependently the GM1 accumulation in lipid rafts to facilitate the aggregation and fibrillation of αSyn (Fig. 7). On the other hand, the phosphorylated αSyn can enhance the oligomerization of αSyn (Liu et al., 2015) and the formation of protofibrils (Fujiwara et al., 2002) through destabilized intramolecular interactions to convert αSyn into folded forms (Sasakawa et al., 2007). In addition, the proteasome inhibitors cause αSyn aggregation and formation of Lewy bodies (Balasuriya et al., 2014). The ER stress response has been reported to promote the fibrillation and aggregation of αSyn (Jiang et al., 2010). Because the ER stress inhibitor reduced the level of αSyn oligomers in 6-month-old σ1R−/− mice, the early increase in the aggregation of αSyn is caused probably by the ER stress, proteasome inactivation, or increased αSyn phosphorylation (Fig. 7).