PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease
In addition to amyloid-[1] 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 mitoc...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Society for Neuroscience
2021
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| Online Access: | https://hdl.handle.net/1721.1/135206 |
| _version_ | 1826192053110833152 |
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| author | Fleck, Daniel Phu, Lilian Verschueren, Erik Hinkle, Trent Reichelt, Mike Bhangale, Tushar Haley, Benjamin Wang, Yuanyuan Graham, Robert Kirkpatrick, Donald S Sheng, Morgan Bingol, Baris |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Fleck, Daniel Phu, Lilian Verschueren, Erik Hinkle, Trent Reichelt, Mike Bhangale, Tushar Haley, Benjamin Wang, Yuanyuan Graham, Robert Kirkpatrick, Donald S Sheng, Morgan Bingol, Baris |
| author_sort | Fleck, Daniel |
| collection | MIT |
| description | In addition to amyloid-[1] 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 (PTCD1) 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. |
| first_indexed | 2024-09-23T09:05:34Z |
| format | Article |
| id | mit-1721.1/135206 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:05:34Z |
| publishDate | 2021 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/1352062023-12-08T20:40:17Z PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease Fleck, Daniel Phu, Lilian Verschueren, Erik Hinkle, Trent Reichelt, Mike Bhangale, Tushar Haley, Benjamin Wang, Yuanyuan Graham, Robert Kirkpatrick, Donald S Sheng, Morgan Bingol, Baris Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory In addition to amyloid-[1] 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 (PTCD1) 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. 2021-10-27T20:22:27Z 2021-10-27T20:22:27Z 2019 2021-03-25T18:37:47Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135206 en 10.1523/JNEUROSCI.0116-19.2019 Journal of Neuroscience Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Society for Neuroscience Journal of Neuroscience |
| spellingShingle | Fleck, Daniel Phu, Lilian Verschueren, Erik Hinkle, Trent Reichelt, Mike Bhangale, Tushar Haley, Benjamin Wang, Yuanyuan Graham, Robert Kirkpatrick, Donald S Sheng, Morgan Bingol, Baris PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease |
| title | PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease |
| title_full | PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease |
| title_fullStr | PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease |
| title_full_unstemmed | PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease |
| title_short | PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease |
| title_sort | ptcd1 is required for mitochondrial oxidative phosphorylation possible genetic association with alzheimer s disease |
| url | https://hdl.handle.net/1721.1/135206 |
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