Revealing the basis of energy metabolic deficiency common to neurodegenerative diseases with differential expression meta-analysis

Abstract Background: The Sry-related high-mobility-group box (SOX) gene family, with 20 known transcription factors in humans, plays essential roles during development and in many disease processes. Several SOX proteins, e.g., SOX4, SOX11, and SOX9, are required for normal heart morphogenesis. SOX9 was shown to contribute to cardiac fibrosis in animal models. However, differential expression of other SOX transcription factors and their functional roles in the failing human myocardium have not been explored.Methods and Findings: All 20 SOX genes from RNA-seq data were extracted, and their RNA levels were compared to the NF, DCM, and hypertrophic cardiomyopathy (HCM) groups. The protein levels of the differential expressed SOX genes were confirmed by Western blot. Four SOX genes whose RNA levels were significantly upregulated in DCM or HCM compared to NF. However, only SOX4 and SOX8 proteins were markedly increased in the heart failure groups. Gene co-expression network analysis identified genes associated and respond similarly to perturbations with SOX4 in cardiac tissues. Using a meta-analysis combining epigenetics and genome-wide association data, we reported several genomic variants associated with HF phenotype linked to SOX4 or SOX8.Conclusions: Elevation of SOX8 and SOX4 are observed in the failing human myocardium. The molecular mechanism associated with them in HF warrants further investigation.

Download Full-text

Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in Down syndrome

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009317 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009317

Author(s):

Ilario De Toma ◽

Cesar Sierra ◽

Mara Dierssen

Keyword(s):

Down Syndrome ◽

Differential Expression ◽

Web Application ◽

Meta Analysis ◽

Chromosome 21 ◽

Complex Disorders ◽

Transcriptomic Data ◽

Genome Wide ◽

A Genome ◽

The Impact

Trisomy of human chromosome 21 (HSA21) causes Down syndrome (DS). The trisomy does not simply result in the upregulation of HSA21--encoded genes but also leads to a genome-wide transcriptomic deregulation, which affect differently each tissue and cell type as a result of epigenetic mechanisms and protein-protein interactions. We performed a meta-analysis integrating the differential expression (DE) analyses of all publicly available transcriptomic datasets, both in human and mouse, comparing trisomic and euploid transcriptomes from different sources. We integrated all these data in a “DS network”. We found that genome wide deregulation as a consequence of trisomy 21 is not arbitrary, but involves deregulation of specific molecular cascades in which both HSA21 genes and HSA21 interactors are more consistently deregulated compared to other genes. In fact, gene deregulation happens in “clusters”, so that groups from 2 to 13 genes are found consistently deregulated. Most of these events of “co-deregulation” involve genes belonging to the same GO category, and genes associated with the same disease class. The most consistent changes are enriched in interferon related categories and neutrophil activation, reinforcing the concept that DS is an inflammatory disease. Our results also suggest that the impact of the trisomy might diverge in each tissue due to the different gene set deregulation, even though the triplicated genes are the same. Our original method to integrate transcriptomic data confirmed not only the importance of known genes, such as SOD1, but also detected new ones that could be extremely useful for generating or confirming hypotheses and supporting new putative therapeutic candidates. We created “metaDEA” an R package that uses our method to integrate every kind of transcriptomic data and therefore could be used with other complex disorders, such as cancer. We also created a user-friendly web application to query Ensembl gene IDs and retrieve all the information of their differential expression across the datasets.

Download Full-text

Differential Expression of Exosomal MicroRNAs in Neurodegenerative Diseases

Role of Exosomes in Biological Communication Systems ◽

10.1007/978-981-15-6599-1_9 ◽

2020 ◽

pp. 207-219

Author(s):

Nesma Elsayed Abdelaal ◽

Mostafa Fathi Abdelhai

Keyword(s):

Neurodegenerative Diseases ◽

Differential Expression

Download Full-text

Occupational Exposures and Neurodegenerative Diseases—A Systematic Literature Review and Meta-Analyses

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16030337 ◽

2019 ◽

Vol 16 (3) ◽

pp. 337 ◽

Cited By ~ 20

Author(s):

Lars-Gunnar Gunnarsson ◽

Lennart Bodin

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Occupational Exposure ◽

Neurodegenerative Diseases ◽

Meta Analysis ◽

Occupational Exposures ◽

Increased Risk ◽

Meta Analyses

Objectives: To carry out an integrated and stratified meta-analysis on occupational exposure to electromagnetic fields (EMFs), metals and pesticides and its effects on amyotrophic lateral sclerosis (ALS) and Parkinson’s and Alzheimer’s disease, and investigate the possibility of publication bias. Methods: In the current study, we updated our recently published meta-analyses on occupational exposures in relation to ALS, Alzheimer’s and Parkinson’s disease. Based on 66 original publications of good scientific epidemiological standard, according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines, we analysed subgroups by carrying out stratified meta-analyses on publication year, statistical precision of the relative risk (RR) estimates, inspection of the funnel plots and test of bias. Results: Based on 19 studies the weighted RR for occupational exposure to EMFs was 1.26 (95% confidence interval (CI) 1.07–1.50) for ALS, 1.33 (95% CI 1.07–1.64) for Alzheimer’s disease and 1.02 (95% CI 0.83–1.26) for Parkinson’s disease. Thirty-one studies concerned occupational exposure to pesticides and the weighted RR was 1.35 (95% CI 1.02–1.79) for ALS, 1.50 (95% CI 0.98–2.29) for Alzheimer’s disease and 1.66 (95% CI 1.42–1.94) for Parkinson’s disease. Finally, 14 studies concerned occupational exposure to metals and only exposure to lead (five studies) involved an elevated risk for ALS or Parkinson’s disease and the weighted RR was 1.57 (95% CI 1.11–2.20). The weighted RR for all the non-lead exposures was 0.97 (95% CI 0.88–1.06). Conclusions: Exposure to pesticides increased the risk of getting the mentioned neurodegenerative diseases by at least 50%. Exposure to lead was only studied for ALS and Parkinson’s disease and involved 50% increased risk. Occupational exposure to EMFs seemed to involve some 10% increase in risk for ALS and Alzheimer’s disease only.

Download Full-text

Genealogy of the neurodegenerative diseases based on a meta-analysis of age-stratified incidence data

Scientific Reports ◽

10.1038/s41598-020-75014-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Daniela Gerovska ◽

Haritz Irizar ◽

David Otaegi ◽

Isidre Ferrer ◽

Adolfo López de Munain ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Meta Analysis ◽

Disease Onset ◽

Epidemiological Studies ◽

Misfolded Proteins ◽

Mathematical Framework ◽

Dynamic Adjustment ◽

Genealogical Tree ◽

Incidence Data ◽

Multistep Model

Abstract While the central common feature of the neurodegenerative diseases (NDs) is the accumulation of misfolded proteins, they share other pathogenic mechanisms. However, we miss an explanation for the onset of the NDs. The mechanisms through which genetic mutations, present from conception are expressed only after several decades of life are unknown. We aim to find clues on the complexity of the disease onset trigger of the different NDs expressed in the number of steps of factors related to a disease. We collected brain autopsies on diseased patients with NDs, and found a dynamic increase of the ND multimorbidity with the advance of age. Together with the observation that the NDs accumulate multiple misfolded proteins, and the same misfolded proteins are involved in more than one ND, motivated us to propose a model for a genealogical tree of the NDs. To collect the dynamic data needed to build the tree, we used a Big-data approach that searched automatically epidemiological datasets for age-stratified incidence of NDs. Based on meta-analysis of over 400 datasets, we developed an algorithm that checks whether a ND follows a multistep model, finds the number of steps necessary for the onset of each ND, finds the number of common steps with other NDs and the number of specific steps of each ND, and builds with these findings a parsimony tree of the genealogy of the NDs. The tree discloses three types of NDs: the stem NDs with less than 3 steps; the trunk NDs with 5 to 6 steps; and the crown NDs with more than 7 steps. The tree provides a comprehensive understanding of the relationship across the different NDs, as well as a mathematical framework for dynamic adjustment of the genealogical tree of the NDs with the appearance of new epidemiological studies and the addition of new NDs to the model, thus setting the basis for the search for the identity and order of these steps. Understanding the complexity, or number of steps, of factors related to disease onset trigger is important prior deciding to study single factors for a multiple steps disease.

Download Full-text

Dietary Pattern Score, Diet Quality, and Major Neurodegenerative Diseases: A Meta-analysis of Observational Cohort Studies (OR33-07-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz039.or33-07-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Yi-Hsuan Liu ◽

Xiang Gao ◽

Muzi Na ◽

Penny Kris-Etherton ◽

Diane Mitchell ◽

...

Keyword(s):

Cohort Studies ◽

Neurodegenerative Diseases ◽

Diet Quality ◽

Dietary Patterns ◽

Dietary Pattern ◽

Meta Analysis ◽

A Priori ◽

A Posteriori ◽

Observational Cohort ◽

Healthy Dietary Pattern

Abstract Objectives Diet is an important lifestyle factor that may prevent or slow the onset and progression of neurodegeneration. Recent studies suggest that adherence to a healthy dietary pattern is associated with reduced risk of cognitive decline. Few studies have examined the relationships between dietary patterns and risk of clinical neurodegenerative disease outcomes. In this meta-analysis, we examined the associations between overall dietary patterns, assessed a priori and a posteriori, and risk of major neurodegenerative disease including dementia, Alzheimer's disease, and Parkinson's disease. Methods We systematically searched in the PubMed, Web of Science, and Cumulative Index for Nursing and Allied Health databases starting from 1981 to October 10, 2018. Observational cohort studies published in English with prospective and case-control designs were included. Diet assessment approaches (a priori or a posteriori) were utilized to assist in determining whether the exposure was dietary pattern score or diet quality. Generic inverse variance method was used to calculate the pooled risk ratios and 95% confidence intervals (CIs) among the highest versus the lowest diet quality/dietary pattern score groups in random effect models. Results Seventeen studies with 173,283 participants were identified. Various diet quality indexes or dietary pattern scores, such as the Healthy Eating Index, the Mediterranean diet score, and dietary pattern scores generated by principal component analysis or reduced rank regression, were used among studies. Our meta-analysis of cohorts showed significant associations between adherence to high diet quality or healthy dietary pattern and lower risk of dementia (pooled risk ratio = 0.70; 95% CI: 0.56-0.86) and Parkinson's disease (pooled risk ratio = 0.72; 95% CI: 0.54-0.97) relative to those with low diet quality or unhealthy dietary pattern. Conclusions Adherence to high diet quality or healthy dietary pattern may provide protective effects on risk of neurodegenerative diseases. Additional observational studies and randomized controlled trials are needed to address our study limitations and provide further evidence about the role of a poor diet on the development and progression of neurodegenerative diseases as well as the benefits of a healthy diet on the prevention of major neurodegenerative diseases. Funding Sources United States Department of Agriculture, Agricultural Research Service agreement. Supporting Tables, Images and/or Graphs

Download Full-text