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PTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease.
Monday,2019-07-29 14:01 America/Los_Angeles — ecterry
| Title | PTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease. |
| Publication Type | Journal Article |
| Year of Publication | 2019 |
| Authors | Fleck, D, Phu, L, Verschueren, E, Hinkle, T, Reichelt, M, Bhangale, T, Haley, B, Wang, Y, Graham, R, Kirkpatrick, DS, Sheng, M, Bingol, B |
| Journal | J Neurosci |
| Volume | 39 |
| Issue | 24 |
| Pagination | 4636-4656 |
| Date Published | 2019 Jun 12 |
| ISSN | 1529-2401 |
| Abstract | <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> |
| DOI | 10.1523/JNEUROSCI.0116-19.2019 |
| Alternate Journal | J. Neurosci. |
| PubMed ID | 30948477 |
| PubMed Central ID | PMC6561697 |
| Grant List | HHSN268201100012C / HL / NHLBI NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States HHSN268201100009I / HL / NHLBI NIH HHS / United States U01 HL096812 / HL / NHLBI NIH HHS / United States U54 AG052427 / AG / NIA NIH HHS / United States R01 NS017950 / NS / NINDS NIH HHS / United States R01 AG054076 / AG / NIA NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States HHSN268201500001C / HL / NHLBI NIH HHS / United States HHSN268201100005G / HL / NHLBI NIH HHS / United States U01 AG049507 / AG / NIA NIH HHS / United States U01 HL096917 / HL / NHLBI NIH HHS / United States HHSN268201100008I / HL / NHLBI NIH HHS / United States U01 AG052411 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States HHSN268201100011I / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States U01 HL096902 / HL / NHLBI NIH HHS / United States UF1 AG047133 / AG / NIA NIH HHS / United States U01 AG057659 / AG / NIA NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States R01 AG049607 / AG / NIA NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States U24 AG041689 / AG / NIA NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States U01 AG049508 / AG / NIA NIH HHS / United States U01 AG052410 / AG / NIA NIH HHS / United States U01 HL096814 / HL / NHLBI NIH HHS / United States R01 AG033040 / AG / NIA NIH HHS / United States U54 HG003079 / HG / NHGRI NIH HHS / United States U01 AG052409 / AG / NIA NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States R01 HL070825 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States U01 HL096899 / HL / NHLBI NIH HHS / United States HHSN268201100007I / HL / NHLBI NIH HHS / United States U01 AG049506 / AG / NIA NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States |
ePub date:
19/06