NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization
NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization
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DOI：
10.1038/ncomms4354
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发表时间：
2014-02
影响因子：
16.6
通讯作者：
T. Yamanaka;A. Tosaki;M. Kurosawa;Gen Matsumoto;M. Koike;Y. Uchiyama;S. Maity;T. Shimogori;N. Hattori;N. Nukina
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文献类型：
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作者：
T. Yamanaka;A. Tosaki;M. Kurosawa;Gen Matsumoto;M. Koike;Y. Uchiyama;S. Maity;T. Shimogori;N. Hattori;N. Nukina
核转录因子-Y(NF-Y)是细胞周期进程的关键调节因子，在分化为非增殖性细胞过程中经常失去活性。相反，核因子-Y在成熟的、分化的神经元中仍然活跃，尽管它在神经元中的意义仍然不清楚。在这里，我们表明，有丝分裂后小鼠神经元中有条件缺失的NF-YA亚单位诱导了具有独特泛素/p62病理特征的进行性神经变性；这些蛋白没有并入丝状包涵体，而是与内质网(ER)上的不溶性膜蛋白共同积累。变性还伴随着严重的内质网紊乱，即核周区无核糖体的内质网异常增加，但不会引发内质网应激反应。我们进一步进行了染色质免疫沉淀，并鉴定了几个NF-Y生理靶点，包括可能参与内质网解体的Grp94。我们认为，核因子-Y参与了成熟神经元内质网组织的一种独特的调节机制，它的破坏导致了以前未被描述的新的神经病理伴随着泛素/p62的异常积聚。
Nuclear transcription factor-Y (NF-Y), a key regulator of cell-cycle progression, often loses its activity during differentiation into nonproliferative cells. In contrast, NF-Y is still active in mature, differentiated neurons, although its neuronal significance remains obscure. Here we show that conditional deletion of the subunit NF-YA in postmitotic mouse neurons induces progressive neurodegeneration with distinctive ubiquitin/p62 pathology; these proteins are not incorporated into filamentous inclusion but co-accumulated with insoluble membrane proteins broadly on endoplasmic reticulum (ER). The degeneration also accompanies drastic ER disorganization, that is, an aberrant increase in ribosome-free ER in the perinuclear region, without inducing ER stress response. We further perform chromatin immunoprecipitation and identify several NF-Y physiological targets including Grp94 potentially involved in ER disorganization. We propose that NF-Y is involved in a unique regulation mechanism of ER organization in mature neurons and its disruption causes previously undescribed novel neuropathology accompanying abnormal ubiquitin/p62 accumulation.