Yamanaka Tomoyuki, Tosaki Asako, Miyazaki Haruko, Kurosawa Masaru, Koike Masato, Uchiyama Yasuo, Maity Sankar N, Misawa Hidemi, Takahashi Ryosuke, Shimogori Tomomi, Hattori Nobutaka, Nukina Nobuyuki
Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, Kyoto 610-0394, Japan.
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Sci Rep. 2016 Sep 30;6:34575. doi: 10.1038/srep34575.
The mammalian central nervous system (CNS) contains various types of neurons with different neuronal functions. In contrast to established roles of cell type-specific transcription factors on neuronal specification and maintenance, whether ubiquitous transcription factors have conserved or differential neuronal function remains uncertain. Here, we revealed that inactivation of a ubiquitous factor NF-Y in different sets of neurons resulted in cell type-specific neuropathologies and gene downregulation in mouse CNS. In striatal and cerebellar neurons, NF-Y inactivation led to ubiquitin/p62 pathologies with downregulation of an endoplasmic reticulum (ER) chaperone Grp94, as we previously observed by NF-Y deletion in cortical neurons. In contrast, NF-Y inactivation in motor neurons induced neuronal loss without obvious protein deposition. Detailed analysis clarified downregulation of another ER chaperone Grp78 in addition to Grp94 in motor neurons, and knockdown of both ER chaperones in motor neurons recapitulated the pathology observed after NF-Y inactivation. Finally, additional downregulation of Grp78 in striatal neurons suppressed ubiquitin accumulation induced by NF-Y inactivation, implying that selective ER chaperone downregulation mediates different neuropathologies. Our data suggest distinct roles of NF-Y in protein homeostasis and neuronal maintenance in the CNS by differential regulation of ER chaperone expression.
哺乳动物的中枢神经系统（CNS）包含具有不同神经元功能的多种类型的神经元。与细胞类型特异性转录因子在神经元特化和维持中的既定作用相反，普遍存在的转录因子是否具有保守或不同的神经元功能仍不确定。在这里，我们发现不同组神经元中普遍存在的因子NF-Y失活导致小鼠中枢神经系统中细胞类型特异性神经病理学和基因下调。在纹状体和小脑神经元中，NF-Y失活导致泛素/p62病理学以及内质网（ER）伴侣蛋白Grp94的下调，正如我们之前在皮质神经元中通过NF-Y缺失所观察到的那样。相比之下，运动神经元中的NF-Y失活诱导神经元丢失而无明显蛋白质沉积。详细分析表明，除了运动神经元中的Grp94外，另一种ER伴侣蛋白Grp78也下调，并且在运动神经元中敲低这两种ER伴侣蛋白可重现NF-Y失活后观察到的病理学现象。最后，纹状体神经元中Grp78的进一步下调抑制了NF-Y失活诱导的泛素积累，这意味着选择性ER伴侣蛋白下调介导了不同的神经病理学现象。我们的数据表明，NF-Y通过对内质网伴侣蛋白表达的差异调节，在中枢神经系统的蛋白质稳态和神经元维持中发挥不同作用。
