Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Cell Death Dis. 2013 Mar 7;4(3):e535. doi: 10.1038/cddis.2013.64.
Heterozygosity for missense mutations (N88S/S90L) in BSCL2 (Berardinelli-Seip congenital lipodystrophy type 2)/Seipin is associated with a broad spectrum of motoneuron diseases. To understand the underlying mechanisms how the mutations lead to motor neuropathy, we generated transgenic mice with neuron-specific expression of wild-type (tgWT) or N88S/S90L mutant (tgMT) human Seipin. Transgenes led to the broad expression of WT or mutant Seipin in the brain and spinal cord. TgMT, but not tgWT, mice exhibited late-onset altered locomotor activities and gait abnormalities that recapitulate symptoms of seipinopathy patients. We found loss of alpha motor neurons in tgMT spinal cord. Mild endoreticular stress was present in both tgMT and tgWT neurons; however, only tgMT mice exhibited protein aggregates and disrupted Golgi apparatus. Furthermore, autophagosomes were significantly increased, along with elevated light chain 3 (LC3)-II level in tgMT spinal cord, consistent with the activation of autophagy pathway in response to mutant Seipin expression and protein aggregation. These results suggest that induction of autophagy pathway is involved in the cellular response to mutant Seipin in seipinopathy and that motoneuron loss is a key pathogenic process underlying the development of locomotor abnormalities.
BSCL2（Berardinelli-Seip 先天性脂肪营养不良 2 型）/Seipin 错义突变（N88S/S90L）的杂合性与广泛的运动神经元疾病有关。为了了解突变导致运动神经病的潜在机制，我们生成了具有神经元特异性表达野生型（tgWT）或 N88S/S90L 突变型（tgMT）人 Seipin 的转基因小鼠。转基因导致 WT 或突变 Seipin 在大脑和脊髓中的广泛表达。TgMT 而不是 tgWT 小鼠表现出运动活动和步态异常的迟发性改变，这些异常重现了 seipinopathy 患者的症状。我们发现 tgMT 脊髓中的 alpha 运动神经元丢失。两种 tgMT 和 tgWT 神经元中均存在轻度内质网应激；然而，只有 tgMT 小鼠表现出蛋白聚集体和高尔基器破坏。此外，自噬体在 tgMT 脊髓中显著增加，同时 LC3-II 水平升高，与突变 Seipin 表达和蛋白聚集体引发自噬途径的激活一致。这些结果表明，自噬途径的诱导参与了运动神经元疾病中突变 Seipin 的细胞反应，运动神经元丢失是运动异常发展的关键致病过程。
