PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease
Name
4636.full.pdf
Description
Published version
Size
5.01 MB
Format
Adobe PDF
Checksum (MD5)
c031c5f43f79a5cc15f42f86a38299ab
Author(s)
Fleck, Daniel
Phu, Lilian
Verschueren, Erik
Hinkle, Trent
Reichelt, Mike
Bhangale, Tushar
Haley, Benjamin
Wang, Yuanyuan
Graham, Robert
Kirkpatrick, Donald S
Date Issued
2019
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1523/JNEUROSCI.0116-19.2019
