Dataset Information

Genetic variation of oxidative phosphorylation genes in stroke and Alzheimer's disease.

ABSTRACT: Previous research implicates alterations in oxidative phosphorylation (OXPHOS) in the development of Alzheimer's disease (AD). We sought to test whether genetic variants within OXPHOS genes increase the risk of AD. We first used gene-set enrichment analysis to identify associations, and then applied a previously replicated stroke genetic risk score to determine if OXPHOS genetic overlap exists between stroke and AD. Gene-set enrichment analysis identified associations between variation in OXPHOS genes and AD versus control status (p = 0.012). Conversion from cognitively normal controls to mild cognitive impairment was also associated with the OXPHOS gene-set (p = 0.045). Subset analyses demonstrated association for complex I genes (p < 0.05), but not for complexes II-V. Among neuroimaging measures, hippocampal volume and entorhinal cortex thickness were associated with OXPHOS genes (all p < 0.025). The stroke genetic risk score demonstrated association with clinical status, baseline and longitudinal imaging measures (p < 0.05). OXPHOS genetic variation influences clinical status and neuroimaging intermediates of AD. OXPHOS genetic variants associated with stroke are also linked to AD progression. Further studies are needed to explore functional consequences of these OXPHOS variants.

SUBMITTER: Biffi A

PROVIDER: S-EPMC4329419 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Genetic variation of oxidative phosphorylation genes in stroke and Alzheimer's disease.

Biffi Alessandro A Sabuncu Mert R MR Desikan Rahul S RS Schmansky Nick N Salat David H DH Rosand Jonathan J Anderson Christopher D CD

Neurobiology of aging 20140205 8

Previous research implicates alterations in oxidative phosphorylation (OXPHOS) in the development of Alzheimer's disease (AD). We sought to test whether genetic variants within OXPHOS genes increase the risk of AD. We first used gene-set enrichment analysis to identify associations, and then applied a previously replicated stroke genetic risk score to determine if OXPHOS genetic overlap exists between stroke and AD. Gene-set enrichment analysis identified associations between variation in OXPHOS ...[more]

PMID: 24650791

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Project description: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 (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.SIGNIFICANCE STATEMENT 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 PTCD1 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.

Dataset Information

Genetic variation of oxidative phosphorylation genes in stroke and Alzheimer's disease.

Publications

Genetic variation of oxidative phosphorylation genes in stroke and Alzheimer's disease.

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