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PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease

ABSTRACT: Besides amyloid-beta 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 remains scarce. We performed whole exome sequencing of AD cases versus controls and discovered that a coding mutation in the gene pentatricopeptide repeat containing protein (PTCD1) is enriched in patients. 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: erik verschueren

PROVIDER: MSV000083232 | MassIVE | Fri Dec 14 15:31:00 GMT 2018

REPOSITORIES: MassIVE

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PTCD1 is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease

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