02966nas a2200277   4500008004100000022001400041245012200055210006900177260001600246300001400262490000700276520213400283100001802417700001602435700002202451700001802473700001902491700002102510700002002531700001902551700001902570700002702589700001802616700001802634856003602652       2019                        eng d  a1529-240100aPTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease.0 aPTCD1 Is Required for Mitochondrial OxidativePhosphorylation Pos  c2019 Jun 12  a4636-46560 v393 a<p>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.</p>1 aFleck, Daniel1 aPhu, Lilian1 aVerschueren, Erik1 aHinkle, Trent1 aReichelt, Mike1 aBhangale, Tushar1 aHaley, Benjamin1 aWang, Yuanyuan1 aGraham, Robert1 aKirkpatrick, Donald, S1 aSheng, Morgan1 aBingol, Baris  uhttps://chs-nhlbi.org/node/8101