TorsinA dysfunction causes persistent neuronal nuclear pore defects.
TorsinA dysfunction causes persistent neuronal nuclear pore defects.
复制标题
TorsinA 功能障碍会导致持续的神经元核孔缺陷。
DOI：
10.1093/hmg/ddx405
复制
发表时间：
2018
影响因子：
3.5
通讯作者：
Dauer,WilliamT
中科院分区：
文献类型：
--
作者：
Pappas,SamuelS;Liang,Chun-Chi;Kim,Sumin;Rivera,CheyAnneO;Dauer,WilliamT
破译神经发育疾病的病理生理学的一个关键挑战是确定在CNS成熟过程中出现的无数异常中，哪些持续导致长期脑功能障碍。由AAA+蛋白torsinA的功能缺失突变引起的儿童期发作的肌张力障碍加剧了这一挑战。缺乏torsinA的神经元在中枢神经系统成熟过程中发生短暂的核膜（NE）畸形，但在成熟的torsinA空神经元中没有NE缺陷。我们发现，在出生后的中枢神经系统成熟torsinA空神经元开发错误定位和功能失调的核孔复合物（NPC），缺乏NUP358，通常添加在NPC生物发生的后期。SUN1，一个与间期NPC生物发生有关的torsinA相关分子，也表现出定位异常。尽管SUN1和相关的核膜异常在幼年小鼠中得到解决，但NPC缺陷持续到成年。这些发现支持了torsinA功能在神经元成熟过程中NPC生物发生中的作用，并暗示了NPC功能在肌张力障碍病理生理学中的改变。
A critical challenge to deciphering the pathophysiology of neurodevelopmental disease is identifying which of the myriad abnormalities that emerge during CNS maturation persist to contribute to long-term brain dysfunction. Childhood-onset dystonia caused by a loss-of-function mutation in the AAA+ protein torsinA exemplifies this challenge. Neurons lacking torsinA develop transient nuclear envelope (NE) malformations during CNS maturation, but no NE defects are described in mature torsinA null neurons. We find that during postnatal CNS maturation torsinA null neurons develop mislocalized and dysfunctional nuclear pore complexes (NPC) that lack NUP358, normally added late in NPC biogenesis. SUN1, a torsinA-related molecule implicated in interphase NPC biogenesis, also exhibits localization abnormalities. Whereas SUN1 and associated nuclear membrane abnormalities resolve in juvenile mice, NPC defects persist into adulthood. These findings support a role for torsinA function in NPC biogenesis during neuronal maturation and implicate altered NPC function in dystonia pathophysiology.