Abstract
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 αSyn oligomers and oligomer phosphorylation (S129), but not αSyn monomers, were elevated in dopaminergic neurons and substantia nigra of seipin-nKO mice. The PPARγ expression in seipin-nKO mice was reduced. In seipin-nKO mice, the phosphorylation of GSK3β was increased at Tyr216 and was reduced at Ser9, which was corrected by the PPARγ agonist rosiglitazone. The increased IL-6 level in seipin-nKO mice was sensitive to rosiglitazone and GSK3β inhibitor AR-A014418. The enhanced phosphorylation of αSyn was prevented by rosiglitazone and AR-A014418, while the increase in αSyn 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 PPARγ to enhance aggregation and phosphorylation of αSyn and neuroinflammation.
Highlights
Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by a neartotal loss of adipose tissue, severe insulin resistance, hypertriglyceridemia, and fatty liver[1,2]
In seipin-nKO mice, the time that mice traversed the beam in beam walking test (BWT) or the latency that mice remained on the rotarod before falling off were affected by genotype (BWT: F(1, 66) = 13.472, P < 0.001; rod with accelerating speed (RT-AS): F(1, 66) = 23.029, P < 0.001; rod with constant speeds (RT-CS): F(1, 66) = 20.707, P < 0.001)
8-M-old and 12-M-old seipin-nKO mice spent a longer time traversing the beam in the BWT (8M: P < 0.05; 12M: P < 0.01) and remained on the rotarod for less time in the rotarod test (RT)-CS (8M: 28 rpm: P < 0.05, 36 rpm: P < 0.05; 12M: 20 rpm: P < 0.05, 28 or 36 rpm: P < 0.01) or RT-AS (8M: P < 0.05; 12M: P < 0.01)
Summary
Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by a neartotal loss of adipose tissue, severe insulin resistance, hypertriglyceridemia, and fatty liver[1,2]. Patients with CGL2 have sensorineural deafness and cognitive disorder[3] by mutation in the Berardinelli-Seip congenital lipodystrophy 2 gene that encodes seipin[4,5]. Heterozygosity for missense mutations (N88S/S90L) in seipin is associated with a broad spectrum of motoneuron diseases, such as seipinopathy[7]. The motor neurons and peripheral motor axons are differentially affected in patients with seipin mutations[8,9]. The overexpression of human seipin mutants in mice caused the death of alpha motor neurons in the spinal cord which was not associated with total loss of adipose tissue[10].
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