High ω3-polyunsaturated fatty acids in fat-1 mice prevent streptozotocin-induced Purkinje cell degeneration through BDNF-mediated autophagy.
High ω3-polyunsaturated fatty acids in fat-1 mice prevent streptozotocin-induced Purkinje cell degeneration through BDNF-mediated autophagy.
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DOI：
10.1038/srep15465
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发表时间：
2015-10-27
影响因子：
4.6
通讯作者：
Kim DW
中科院分区：
文献类型：
--
作者：
Bak DH;Zhang E;Yi MH;Kim DK;Lim K;Kim JJ;Kim DW
浦肯野细胞的丧失与糖尿病神经病变的发展有关，这种变性的特点是自噬过程受损。我们评估了 fat-1 转基因小鼠（一种内源性合成 ω3 多不饱和脂肪酸 (ω3-PUFA) 的成熟动物模型）在链脲佐菌素 (STZ) 处理的 fat-1 小鼠模型中是否能免受浦肯野细胞变性的影响。 STZ 治疗的 fat-1 小鼠没有出现高血糖、运动缺陷或浦肯野细胞丢失。 STZ处理的野生型小鼠小脑中LC3 I、II、Beclin-1和p62的表达增加，并且这些表达在STZ处理的fat-1小鼠中增加更多，但p62的表达没有增加。此外，在 STZ 处理的 fat-1 小鼠中，小脑 Rab7、组织蛋白酶 D 和 ATP6E 增加。 Fat-1 小鼠小脑中浦肯野细胞中的 BDNF 表达也有所增加，但 TrkB 以及 Akt 和 CREB 的磷酸化没有任何变化。总的来说，这些发现表明，STZ 处理的 fat-1 小鼠免受浦肯野细胞损失的影响，并表现出增加的 BDNF 信号传导，增强小脑浦肯野神经元的自噬流活性。这些过程可能是浦肯野细胞存活的基础，并且可能是治疗与糖尿病神经病变相关的运动缺陷的潜在治疗靶标。
Loss of Purkinje cells has been implicated in the development of diabetic neuropathy, and this degeneration is characterized by impairment of autophagic processes. We evaluated whether fat-1 transgenic mice, a well-established animal model that endogenously synthesizes ω3 polyunsaturated fatty acids (ω3-PUFA), are protected from Purkinje cell degeneration in streptozotocin (STZ)-treated model with fat-1 mice. STZ-treated fat-1 mice did not develop hyperglycemia, motor deficits, or Purkinje cell loss. The expression of LC3 I, II, Beclin-1 and p62 were increased in the cerebellum of STZ-treated wild-type mice, and these expressions were more increased in STZ-treated fat-1 mice, but not of p62. Moreover, cerebellar Rab7, Cathepsin D, and ATP6E were increased in STZ-treated fat-1 mice. There was also increased BDNF expression in Purkinje cells without any changes in TrkB, and phosphorylation of Akt and CREB in the cerebellums of fat-1 mice. Collectively, these findings indicate that STZ-treated fat-1 mice were protected from Purkinje cell loss and exhibited increased BDNF signaling, enhancing autophagic flux activity in cerebellar Purkinje neurons. These processes may underlie Purkinje cell survival and may be potential therapeutic targets for treatment of motor deficits related to diabetic neuropathy.