Departments of Neuroscience.
Microchemistry, Proteomics, and Lipidomics.
J Neurosci. 2019 Jun 12;39(24):4636-4656. doi: 10.1523/JNEUROSCI.0116-19.2019. Epub 2019 Apr 4.
In addition to amyloid-β plaques and tau tangles, mitochondrial dysfunction is implicated in the pathology of Alzheimer's disease (AD). Neurons heavily rely on mitochondrial function, and deficits in brain energy metabolism are detected early in AD; however, direct human genetic evidence for mitochondrial involvement in AD pathogenesis is limited. We analyzed whole-exome sequencing data of 4549 AD cases and 3332 age-matched controls and discovered that rare protein altering variants in the gene pentatricopeptide repeat-containing protein 1 () show a trend for enrichment in cases compared with controls. We show here that PTCD1 is required for normal mitochondrial rRNA levels, proper assembly of the mitochondrial ribosome and hence for mitochondrial translation and assembly of the electron transport chain. Loss of PTCD1 function impairs oxidative phosphorylation and forces cells to rely on glycolysis for energy production. Cells expressing the AD-linked variant of PTCD1 fail to sustain energy production under increased metabolic stress. In neurons, reduced PTCD1 expression leads to lower ATP levels and impacts spontaneous synaptic activity. Thus, our study uncovers a possible link between a protein required for mitochondrial function and energy metabolism and AD risk. Mitochondria are the main source of cellular energy and mitochondrial dysfunction is implicated in the pathology of Alzheimer's disease (AD) and other neurodegenerative disorders. Here, we identify a variant in the gene that is enriched in AD patients and demonstrate that PTCD1 is required for ATP generation through oxidative phosphorylation. PTCD1 regulates the level of 16S rRNA, the backbone of the mitoribosome, and is essential for mitochondrial translation and assembly of the electron transport chain. Cells expressing the AD-associated variant fail to maintain adequate ATP production during metabolic stress, and reduced PTCD1 activity disrupts neuronal energy homeostasis and dampens spontaneous transmission. Our work provides a mechanistic link between a protein required for mitochondrial function and genetic AD risk.
除了淀粉样β斑块和 tau 缠结外，线粒体功能障碍也与阿尔茨海默病（AD）的病理学有关。神经元严重依赖线粒体功能，AD 早期就检测到大脑能量代谢缺陷；然而，直接的人类遗传证据表明线粒体参与 AD 的发病机制是有限的。我们分析了 4549 例 AD 病例和 3332 名年龄匹配的对照者的全外显子组测序数据，发现基因 pentatricopeptide repeat-containing protein 1 ()中的罕见蛋白质改变变异在病例中比对照者有富集的趋势。我们在这里表明，PTCD1 是正常线粒体 rRNA 水平、线粒体核糖体的正确组装所必需的，因此也是线粒体翻译和电子传递链组装所必需的。PTCD1 功能丧失会损害氧化磷酸化作用，并迫使细胞依赖糖酵解产生能量。表达 AD 相关变异体的细胞在增加代谢应激下无法维持能量产生。在神经元中，PTCD1 表达减少导致 ATP 水平降低，并影响自发突触活动。因此，我们的研究揭示了一种与线粒体功能和能量代谢以及 AD 风险相关的蛋白质之间的可能联系。线粒体是细胞能量的主要来源，线粒体功能障碍与阿尔茨海默病（AD）和其他神经退行性疾病的病理学有关。在这里，我们确定了基因中的一个变体在 AD 患者中富集，并证明了 PTCD1 是通过氧化磷酸化产生 ATP 所必需的。PTCD1 调节 16S rRNA 的水平，16S rRNA 是线粒体核糖体的骨干，对于线粒体翻译和电子传递链的组装是必不可少的。表达 AD 相关变异体的细胞在代谢应激期间无法维持足够的 ATP 产生，而降低的 PTCD1 活性会破坏神经元的能量平衡并抑制自发传递。我们的工作为一种与线粒体功能相关的蛋白质与遗传性 AD 风险之间提供了一个机制上的联系。
