Braun Ralf J, Sommer Cornelia, Leibiger Christine, Gentier Romina J G, Dumit Verónica I, Paduch Katrin, Eisenberg Tobias, Habernig Lukas, Trausinger Gert, Magnes Christoph, Pieber Thomas, Sinner Frank, Dengjel Jörn, van Leeuwen Fred W, Kroemer Guido, Madeo Frank
Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany.
Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
Cell Rep. 2015 Mar 10;10(9):1557-1571. doi: 10.1016/j.celrep.2015.02.009. Epub 2015 Mar 5.
Neuronal accumulation of UBB, a frameshift variant of ubiquitin B, is a hallmark of Alzheimer's disease (AD). How UBB contributes to neuronal dysfunction remains elusive. Here, we show that in brain regions of AD patients with neurofibrillary tangles UBB co-exists with VMS1, the mitochondrion-specific component of the ubiquitin-proteasome system (UPS). Expression of UBB in yeast disturbs the UPS, leading to mitochondrial stress and apoptosis. Inhibiting UPS activity exacerbates while stimulating UPS by the transcription activator Rpn4 reduces UBB-triggered cytotoxicity. High levels of the Rpn4 target protein Cdc48 and its cofactor Vms1 are sufficient to relieve programmed cell death. We identified the UBB-induced enhancement of the basic amino acids arginine, ornithine, and lysine at mitochondria as a decisive toxic event, which can be reversed by Cdc48/Vms1-mediated proteolysis. The fact that AD-induced cellular dysfunctions can be avoided by UPS activity at mitochondria has potentially far-reaching pathophysiological implications.
泛素B的移码变体UBB在神经元中的积累是阿尔茨海默病（AD）的一个标志。UBB如何导致神经元功能障碍仍不清楚。在这里，我们表明，在患有神经原纤维缠结的AD患者的脑区中，UBB与泛素蛋白酶体系统（UPS）的线粒体特异性成分VMS1共存。UBB在酵母中的表达会干扰UPS，导致线粒体应激和细胞凋亡。抑制UPS活性会加剧这种情况，而通过转录激活因子Rpn4刺激UPS则会降低UBB引发的细胞毒性。高水平的Rpn4靶蛋白Cdc48及其辅助因子Vms1足以缓解程序性细胞死亡。我们确定UBB诱导的线粒体中碱性氨基酸精氨酸、鸟氨酸和赖氨酸的增加是一个决定性的毒性事件，这可以通过Cdc48/Vms1介导的蛋白水解作用来逆转。线粒体处的UPS活性可以避免AD诱导的细胞功能障碍，这一事实具有潜在的深远病理生理学意义。
