Regional protein expression in human Alzheimer’s brain correlates with disease severity

Xu, Jiaolong; Patassini, Stefano; Rustogi, Nitin; Riba-Garcia, Isabel; Hale, Benjamin D.; Phillips, Alexander M.; Waldvogel, Henry J.; Haines, Robert; Bradbury, Phil; Stevens, Adam; Faull, Richard L.M.; Dowsey, Andrew W.; Cooper, Garth J. S.; Unwin, Richard D.

doi:10.1038/s42003-018-0254-9

Cited by 143 publications

(112 citation statements)

References 74 publications

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“…Studies of functional MRI have reported network-based degeneration in the cerebellum of AD patients [57, 58]. Additionally, a comprehensive proteome study suggested that the cerebellum is affected by different pathways compared to the other brain regions [59]. Our above result may reflect the specificity of the cerebellum.…”

Section: Discussionmentioning

confidence: 60%

Enhancer variants associated with Alzheimer’s disease affect gene expression via chromatin looping

et al. 2019

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Background Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) that may be genetic factors underlying Alzheimer’s disease (AD). However, how these AD-associated SNPs (AD SNPs) contribute to the pathogenesis of this disease is poorly understood because most of them are located in non-coding regions, such as introns and intergenic regions. Previous studies reported that some disease-associated SNPs affect regulatory elements including enhancers. We hypothesized that non-coding AD SNPs are located in enhancers and affect gene expression levels via chromatin loops. Methods To characterize AD SNPs within non-coding regions, we extracted 406 AD SNPs with GWAS p-values of less than 1.00 × 10− 6 from the GWAS catalog database. Of these, we selected 392 SNPs within non-coding regions. Next, we checked whether those non-coding AD SNPs were located in enhancers that typically regulate gene expression levels using publicly available data for enhancers that were predicted in 127 human tissues or cell types. We sought expression quantitative trait locus (eQTL) genes affected by non-coding AD SNPs within enhancers because enhancers are regulatory elements that influence the gene expression levels. To elucidate how the non-coding AD SNPs within enhancers affect the gene expression levels, we identified chromatin-chromatin interactions by Hi-C experiments. Results We report the following findings: (1) nearly 30% of non-coding AD SNPs are located in enhancers; (2) eQTL genes affected by non-coding AD SNPs within enhancers are associated with amyloid beta clearance, synaptic transmission, and immune responses; (3) 95% of the AD SNPs located in enhancers co-localize with their eQTL genes in topologically associating domains suggesting that regulation may occur through chromatin higher-order structures; (4) rs1476679 spatially contacts the promoters of eQTL genes via CTCF-CTCF interactions; (5) the effect of other AD SNPs such as rs7364180 is likely to be, at least in part, indirect through regulation of transcription factors that in turn regulate AD associated genes. Conclusion Our results suggest that non-coding AD SNPs may affect the function of enhancers thereby influencing the expression levels of surrounding or distant genes via chromatin loops. This result may explain how some non-coding AD SNPs contribute to AD pathogenesis.

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Section: Discussionmentioning

confidence: 60%

Enhancer variants associated with Alzheimer’s disease affect gene expression via chromatin looping

et al. 2019

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“…Furthermore, a recent study identified a specific reduction of tRNA synthetases in the cerebellum of AD patients by mass spectrometry [53]. Consistent with dysfunctional ribosomes and impairment in protein synthesis being early events in AD pathogenesis [54], a reduction of tRNA synthetases could directly lead to a reduction of protein synthesis required for learning and memory in AD, but may also exacerbate the pathology via tRNA-induced ribosomal stalling, to be discussed in detail below.…”

Section: Translational Dysregulation In Neurological Disordersmentioning

confidence: 96%

Translation from the Ribosome to the Clinic: Implication in Neurological Disorders and New Perspectives from Recent Advances

et al. 2019

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De novo protein synthesis by the ribosome and its multitude of co-factors must occur in a tightly regulated manner to ensure that the correct proteins are produced accurately at the right time and, in some cases, also in the proper location. With novel techniques such as ribosome profiling and cryogenic electron microscopy, our understanding of this basic biological process is better than ever and continues to grow. Concurrently, increasing attention is focused on how translational regulation in the brain may be disrupted during the progression of various neurological disorders. In fact, translational dysregulation is now recognized as the de facto pathogenic cause for some disorders. Novel mechanisms including ribosome stalling, ribosome-associated quality control, and liquid-liquid phase separation are closely linked to translational regulation, and may thus be involved in the pathogenic process. The relationships between translational dysregulation and neurological disorders, as well as the ways through which we may be able to reverse those detrimental effects, will be examined in this review.

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“…Two recent studies have aimed to fill this knowledge gap. Xu et al (44) performed the most extensive analysis of proteomic changes in the AD brain that are associated with selective vulnerability. They compared protein expression in three highly affected regions (hippocampus, entorhinal cortex, and cingulate gyrus), two lightly affected regions (sensory cortex and motor cortex), and one comparatively unaffected region (cerebellum).…”

Section: The Use Of Proteomics To Understand Selective Vulnerabilitymentioning

confidence: 99%

Using Proteomics to Understand Alzheimer’s Disease Pathogenesis

Drummond

Wısnıewskı

2019

Alzheimer’s Disease

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Our current understanding of the molecular changes that drive Alzheimer' s disease (AD) pathogenesis is incomplete. Unbiased, massspectrometry-based proteomic studies provide an efficient and comprehensive way to quantitatively examine thousands of proteins at once using microscopic amounts of human brain tissue. Recently, the number of proteomic studies that examine protein changes in AD brain tissue has been increasing. This chapter reviews the different proteomic approaches currently being used to identify pathological protein changes in AD brain tissue including bulk tissue studies that examine protein changes throughout the progression of AD, studies of the insoluble proteome in AD, studies using proteomics to examine selective vulnerability in AD, studies of the amyloid plaque and neurofibrillary tangle proteome, studies of the synaptic proteome, and studies of the interactome of beta amyloid and tau. Combined, these complementary proteomic approaches provide increased understanding about the protein changes that occur in the AD brain. Results from these proteomic studies provide an excellent resource for future hypothesisdriven targeted studies and will help identify new biomarkers of disease and new drug targets for AD.

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Regional protein expression in human Alzheimer’s brain correlates with disease severity

Cited by 143 publications

References 74 publications

Enhancer variants associated with Alzheimer’s disease affect gene expression via chromatin looping

Enhancer variants associated with Alzheimer’s disease affect gene expression via chromatin looping

Translation from the Ribosome to the Clinic: Implication in Neurological Disorders and New Perspectives from Recent Advances

Using Proteomics to Understand Alzheimer’s Disease Pathogenesis

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