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Identification of functional regulatory variants implicates distinct transcriptional networks in dementia

ABSTRACT: We used 2 massively parallel reporter assays to characterize 5,706 unique noncoding genetic variants derived from genome-wide association studies for two neurodegenerative disorders: Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP). Specifically, we synthesized a library consisting of both alleles of each SNV embedded within their native genomic context, which was cloned upstream of a minimal promoter within an expression vector. We then measured the transcriptional drive of each library element using next-generation sequencing of barcoded transcripts uniquely associated with each regulatory element. This enabled the identification of variants with significant transcriptional skew between alleles representing likely functional regulatory variants underlying disease risk.

ORGANISM(S): Escherichia coli Homo sapiens

PROVIDER: GSE163855 | GEO | 2020/12/25

REPOSITORIES: GEO

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Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism, and cognitive decline caused by degeneration in specific areas of the brain including globus pallidus (GP), substantia nigra, and subthalamic nucleus. However, the pathogenetic mechanism of PSP remains unclear to date. Unbiased global proteome analysis of patients’ brain samples is an important step toward understanding PSP pathogenesis, as proteins serve as workhorses and building blocks of the cell. In this study, we conducted unbiased mass spectrometry-based global proteome analysis of GP samples from 15 PSP patients, 15 Parkinson disease (PD) patients, and 15 healthy control (HC) individuals. To analyze 45 samples, we conducted 5 batches of 11-plex isobaric tandem mass tag (TMT)-based multiplexing experiments, identifying 10,231 proteins. The gene set enrichment analysis results showed that the PD pathway was the most highly enriched, followed by pathways for oxidative phosphorylation, Alzheimer disease, Huntington disease, and non-alcoholic fatty liver disease (NAFLD) when PSP was compared to HC or PD. Most of the proteins enriched in the gene set enrichment analysis were mitochondrial proteins such as cytochrome c oxidase, NADH dehydrogenase, acyl carrier protein, succinate dehydrogenase, ADP/ATP translocase, cytochrome b-c1 complex, and/or ATP synthase. Strikingly, all of the enriched mitochondrial proteins in the PD pathway were downregulated in PSP compared to both HC and PD. The subsequent Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) protein-protein interaction (PPI) analysis and the weighted gene co-expression network analysis (WGCNA) further supported that the mitochondrial proteins were the most highly enriched in PSP. This is the first global proteome analysis of human GP from PSP patients, and this study paves the way to understanding the pathogenesis mechanism of PSP.

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Identification of functional regulatory variants implicates distinct transcriptional networks in dementia

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