Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, 00185 Rome, Italy.
Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy.
Int J Mol Sci. 2021 Apr 3;22(7):3746. doi: 10.3390/ijms22073746.
The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer's disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.
蛋白质 O-GlcNAc 修饰的紊乱似乎是大脑代谢改变与神经退行性病变进展之间的一个可能联系。正如在阿尔茨海默病 (AD) 大脑中观察到的那样，大脑葡萄糖摄取的缺陷会转化为蛋白质 O-GlcNAc 修饰的减少，从而促进病理性特征的形成。高脂肪饮食 (HFD) 已知会促进大脑代谢失调和胰岛素抵抗，并且这种影响与认知表现下降有关。值得注意的是，异常的蛋白质 O-GlcNAc 修饰可能通过触发 AD 特征和线粒体损伤在 HFD 相关认知能力下降中发挥重要作用。我们的数据支持高脂肪饮食（HFD）处理 6 周的小鼠大脑和我们在 SH-SY5Y 细胞中的体外转位中总蛋白质 O-GlcNAc 修饰谱的损伤。蛋白质 O-GlcNAc 修饰的减少与过食引起的胰岛素抵抗（即胰岛素信号缺陷和线粒体活性降低）有关，这促进了己糖胺生物合成途径（HBP）通量的失调，通过 AMPK 驱动的 GFAT1 激活减少。此外，我们观察到 HFD 诱导 O-GlcNAc 化 tau 和 O-GlcNAc 化 Complex I 亚基 NDUFB8 的选择性损伤，分别导致 tau 毒性和呼吸链功能降低，突出了这种翻译后修饰在神经退行性过程中的作用。
