class='head no_bottom_margin' id='sec1title'>Int'/> Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin
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Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin

机译:线粒体中碱性氨基酸的积累决定了异常泛素的细胞毒性。

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class="head no_bottom_margin" id="sec1title">IntroductionUBB+1, a loss-of-function variant of ubiquitin B (UBB), accumulates in neurofibrillary tangles, a pathological hallmark in Alzheimer’s disease (AD) (). UBB+1 is translated from an aberrant mRNA encoding a +1 frameshift protein in which the C-terminal glycine residue required for ubiquitylation is replaced by an extension of 20 amino acids (). The detrimental impact of UBB+1 has been studied in neuronal cell cultures, transgenic mice, and yeast (). UBB+1 is a substrate for truncation, ubiquitylation, and proteasomal degradation (). Whereas the ubiquitin-proteasome system (UPS) can assure the degradation of low levels of UBB+1, higher levels impair the UPS and subvert the homeostatic mechanisms allowing for its elimination (). At high levels, UBB+1 affects mitochondrial dynamics and triggers neuronal cell death () through as-yet elusive mechanisms.Yeast is an established model for studying programmed cell death mechanisms that are often shared with animal cells, including the contribution of caspases and mitochondrion-associated cell death proteins, such as cytochrome c (). Yeast models have been used to explore cell killing by neurotoxic proteins, such as Parkinson-disease-associated α-synuclein, and the outcome could be successfully translated to fly, worm, and murine disease models, as well as to human disease ().Driven by these premises, we established a yeast cell death model for UBB+1-triggered neurotoxicity. Our findings revealed that UBB+1 interfered with the UPS and triggered the perturbation of the mitochondrion-associated basic amino acid synthesis executing cell death. The mitochondrion-associated UPS subroutine, depending on the AAA-ATPase Cdc48 and its co-factor Vms1, strongly antagonized UBB+1 cytotoxicity. Since VMS1, the human homolog of yeast Vms1, co-exists with UBB+1 in neurofibrillary tangles, these data imply a potential pivotal role of the UPS at mitochondria in AD.
机译:<!-fig ft0-> <!-fig @ position =“ anchor” mode =文章f4-> <!-fig mode =“ anchred” f5-> <!-fig / graphic | fig / alternatives / graphic mode =“ anchored” m1-> class =“ head no_bottom_margin” id =“ sec1title”>简介 UBB +1 ,一种功能丧失的变体泛素B(UBB)聚集在神经原纤维缠结中,这是阿尔茨海默氏病(AD)的病理标志。 UBB +1 是从编码+1移码蛋白的异常mRNA翻译而来的,其中泛素化所需的C端甘氨酸残基被20个氨基酸的延伸所取代()。已经在神经细胞培养,转基因小鼠和酵母菌中研究了UBB +1 的有害影响。 UBB +1 是截短,泛素化和蛋白酶体降解的底物()。泛素-蛋白酶体系统(UPS)可以确保低水平的UBB +1 的降解,而更高的水平会损害UPS,并破坏体内平衡​​机制,从而消除它()。在高水平下,UBB +1 会通过迄今难以捉摸的机制影响线粒体动力学并触发神经元细胞死亡。酵母是建立模型,用于研究通常与动物细胞共享的程序性细胞死亡机制,包括胱天蛋白酶和线粒体相关的细胞死亡蛋白,例如细胞色素c()的贡献。酵母模型已被用于探索神经毒性蛋白(如帕金森病相关的α-突触核蛋白)对细胞的杀伤作用,其结果可成功转化为蝇,蠕虫和鼠类疾病模型以及人类疾病()。在这些前提下,我们建立了UBB +1 触发的神经毒性的酵母细胞死亡模型。我们的发现表明,UBB +1 干扰了UPS,并触发了线粒体相关的碱性氨基酸合成,从而导致细胞死亡。线粒体相关的UPS子程序依赖于AAA-ATPase Cdc48及其辅因子Vms1,强烈拮抗UBB +1 的细胞毒性。由于酵母Vms1的人类同源物VMS1与UBB +1 在神经原纤维缠结中共存,因此这些数据暗示了UPS在AD线粒体中的潜在关键作用。

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