Peroxisome biogenesis deficiency attenuates the BDNF-TrkB pathway-mediated development of the cerebellum
Peroxisome biogenesis deficiency attenuates the BDNF-TrkB pathway-mediated development of the cerebellum
复制标题
DOI：
10.26508/lsa.201800062
复制
发表时间：
2018-12-01
影响因子：
4.4
通讯作者：
Fujiki, Yukio
中科院分区：
文献类型：
--
作者：
Abe, Yuichi;Honsho, Masanori;Fujiki, Yukio
过氧化物酶体生物发生障碍（PBD）表现为中枢神经系统中的神经缺陷，包括神经元迁移缺陷和小脑异常的发育。然而，发病机理的基础机制仍然神秘。在这里，为了研究过氧化物酶体缺乏如何导致PBD的神经缺陷，我们在过氧化物酶体组装因子PEX14P中建立了一种新的PBD模型，称为PEX14（Delta C/Delta C）小鼠。 PEX14（Delta C/Delta C）小鼠表现出严重的症状，例如皮质层状结构的混乱和出生后不久死亡，尽管过氧化物酶体生物发生和代谢是部分缺陷。 PEX14（Delta c/delta c）小鼠还显示了小脑的畸形，包括Purkinje细胞的树突状发育受损。此外，细胞外信号调节的激酶和AKT信号传导通过脑衍生的神经营养因子（BDNF）的水平升高，加上TRKB-T1的增强表达，TRKB-T1的表达是BDNF受体的显性阴性同工型。我们的结果表明，BDNF-TRKB途径的失调是小脑形态发生的基本信号，导致PBD中小脑的发病机理。
Peroxisome biogenesis disorders (PBDs) manifest as neurological deficits in the central nervous system, including neuronal migration defects and abnormal cerebellum development. However, the mechanisms underlying pathogenesis remain enigmatic. Here, to investigate how peroxisome deficiency causes neurological defects of PBDs, we established a new PBD model mouse defective in peroxisome assembly factor Pex14p, termed Pex14(Delta C/Delta C) mouse. Pex14(Delta C/Delta C) mouse manifests a severe symptom such as disorganization of cortical laminar structure and dies shortly after birth, although peroxisomal biogenesis and metabolism are partially defective. The Pex14(Delta C/Delta C) mouse also shows malformation of the cerebellum including the impaired dendritic development of Purkinje cells. Moreover, extracellular signal-regulated kinase and AKT signaling are attenuated in this mutant mouse by an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, a dominant-negative isoform of the BDNF receptor. Our results suggest that dysregulation of the BDNF-TrkB pathway, an essential signaling for cerebellar morphogenesis, gives rise to the pathogenesis of the cerebellum in PBDs.