CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines
CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines
复制标题
DOI：
10.1242/jcs.068817
复制
发表时间：
2010-09-01
影响因子：
4
通讯作者：
Goldberg, Yves
中科院分区：
文献类型：
--
作者：
Belly, Agnes;Bodon, Gilles;Goldberg, Yves
高度保守的ESCRT-III复合物负责内体运输和其他细胞活动期间膜的变形和切割。在人类中，ESCRT-III亚基CHMP 2B中的显性突变导致额颞叶痴呆（FTD）。导致这种皮质退化的长达十年的过程尚不清楚。一种可能性是，与其他神经退行性疾病类似，致病蛋白在任何神经元死亡之前影响树突棘和突触的完整性。使用共聚焦显微镜和3D重建，我们研究了在培养的海马神经元中表达FTD连锁突变体CHMP 2B（内含子5）和CHMP 2B（Delta 10）是否改变了棘的数量或结构。这两种突变体诱导蘑菇形态的大刺的比例显着下降，没有明显的退化。此外，CHMP 2B（Delta 10）诱导自发兴奋性突触后电流的频率和振幅下降，表明失去了更有效的突触。这些影响似乎与自噬的变化无关。通过RNAi消耗内源CHMP 2B导致与突变体CHMP 2B诱导的形态学变化相似的形态学变化，与致病突变体的显性负活性一致。因此，CHMP 2B是脊柱生长所必需的。总之，这些结果表明，突变ESCRT-III亚基连接到人类神经退行性疾病可以破坏脊柱发育的正常模式。
The highly conserved ESCRT-III complex is responsible for deformation and cleavage of membranes during endosomal trafficking and other cellular activities. In humans, dominant mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD). The decade-long process leading to this cortical degeneration is not well understood. One possibility is that, akin to other neurodegenerative diseases, the pathogenic protein affects the integrity of dendritic spines and synapses before any neuronal death. Using confocal microscopy and 3D reconstruction, we examined whether expressing the FTD-linked mutants CHMP2B(intron5) and CHMP2B(Delta 10) in cultured hippocampal neurons modified the number or structure of spines. Both mutants induced a significant decrease in the proportion of large spines with mushroom morphology, without overt degeneration. Furthermore, CHMP2B(Delta 10) induced a drop in frequency and amplitude of spontaneous excitatory postsynaptic currents, suggesting that the more potent synapses were lost. These effects seemed unrelated to changes in autophagy. Depletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant-negative activity of pathogenic mutants. Thus, CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development.