Seipin deficiency in mice causes loss of dopaminergic neurons via aggregation and phosphorylation of α-synuclein and neuroinflammation

Seipin gene is originally found in type 2 congenital generalized lipodystrophy (CGL2) to involve lipid droplet formation. Recently, decrease of seipin expression is reported in substantia nigra of Parkinson's disease patients. Dopaminergic neurons in substantia nigra pars compacta expressed the seipin protein. The objective of this study is to investigate influence of the seipin deficiency on dopaminergic neurons and motor behaviors. Neuronal seipin knockout (seipin-nKO) mice (3-12 months of age) displayed an age-related deficit in motor coordination. The number of dopaminergic neurons in seipin-nKO mice was age dependently reduced with increase in cleaved caspase-3. The levels of aSyn oligomers and oligomer phosphorylation (S129), but not aSyn monomers, were elevated in dopaminergic neurons and substantia nigra of seipin-nKO mice. The PPAR. expression in seipin-nKO mice was reduced. In seipin-nKO mice, the phosphorylation of GSK3 beta was increased at Tyr216 and was reduced at Ser9, which was corrected by the PPAR. agonist rosiglitazone. The increased IL-6 level in seipin-nKO mice was sensitive to rosiglitazone and GSK3 beta inhibitor AR-A014418. The enhanced phosphorylation of aSyn was prevented by rosiglitazone and ARA014418, while the increase in aSyn oligomers was corrected only by rosiglitazone. The treatment of seipin-nKO mice with rosiglitazone and AR-A014418 rescued the death of dopaminergic neurons, which was accompanied by the improvement of motor coordination. Therefore, the results indicate that seipin deficiency causes an age-related loss of dopaminergic neurons and impairment of motor coordination through reducing PPAR. to enhance aggregation and phosphorylation of aSyn and neuroinflammation.