Common Factors in Neurodegeneration: A Meta-Study Revealing Shared Patterns on a Multi-Omics Scale

Abstract

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are heterogeneous, progressive diseases with frequently overlapping symptoms characterized by a loss of neurons. Studies have suggested relations between neurodegenerative diseases for many years (e.g., regarding the aggregation of toxic proteins or triggering endogenous cell death pathways). We gathered publicly available genomic, transcriptomic, and proteomic data from 177 studies and more than one million patients to detect shared genetic patterns between the neurodegenerative diseases on three analyzed omics-layers. The results show a remarkably high number of shared differentially expressed genes between the transcriptomic and proteomic levels for all conditions, while showing a significant relation between genomic and proteomic data between AD and PD and AD and ALS. We identified a set of 139 genes being differentially expressed in several transcriptomic experiments of all four diseases. These 139 genes showed overrepresented gene ontology (GO) Terms involved in the development of neurodegeneration, such as response to heat and hypoxia, positive regulation of cytokines and angiogenesis, and RNA catabolic process. Furthermore, the four analyzed neurodegenerative diseases (NDDs) were clustered by their mean direction of regulation throughout all transcriptomic studies for this set of 139 genes, with the closest relation regarding this common gene set seen between AD and HD. GO-Term and pathway analysis of the proteomic overlap led to biological processes (BPs), related to protein folding and humoral immune response. Taken together, we could confirm the existence of many relations between Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis on transcriptomic and proteomic levels by analyzing the pathways and GO-Terms arising in these intersections. The significance of the connection and the striking relation of the results to processes leading to neurodegeneration between the transcriptomic and proteomic data for all four analyzed neurodegenerative diseases showed that exploring many studies simultaneously, including multiple omics-layers of different neurodegenerative diseases simultaneously, holds new relevant insights that do not emerge from analyzing these data separately. Furthermore, the results shed light on processes like the humoral immune response that have previously been described only for certain diseases. Our data therefore suggest human patients with neurodegenerative diseases should be addressed as complex biological systems by integrating multiple underlying data sources.

Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases

“…The evidence documented here shows that a deeper understanding of NDs based on multi-omics levels may prompt a shift toward their molecular classification, highlighting both the intrinsic heterogeneity of the pathologies and the differences in involved molecular pathways, as well as the relationships and connections inside the neurodegenerative process itself. Gathering multi omics-layers (genomic, transcriptomic and proteomic data) from 177 studies and more than one million patients suffering AD, PD, Huntington’s disease (HD) and ALS has recently shown a remarkably high number of shared differentially expressed genes between the transcriptomic and proteomic levels for all conditions, shedding light on processes like the humoral immune response, that have previously been described only for certain diseases [ 101 ]. An accurate investigation of complex biological systems by integrating multiple underlying data sources may help to detect shared genetic patterns between the neurodegenerative diseases, identifying biomarkers for differentiating disease states and thereby facilitating the decision-making process and treatment management.…”

Mass Spectrometry for Neurobiomarker Discovery: The Relevance of Post-Translational Modifications

“…Integrative proteomic and genomic/transcriptomic analyses (in neuroproteogenomics settings) hold great promise for understanding the role of the PTMome in neurodegenerative diseases. For example, a multi-omics data fusion from 177 studies and more than one million patients with AD, PD, HD, and ALS has recently shed light on different biological processes between these pathologies [148]. However, PTMome information was not considered in this integrative study.…”

A Systematic Review of Transcriptional Dysregulation in Huntington’s Disease Studied by RNA Sequencing

“…Protein misfolding is one of the hallmarks in not only HD but also is associated with other neurodegenerative disorders like Alzheimer's Disease (AD), Parkinson's Disease (PD) and amyotrophic lateral sclerosis (ALS). Ruffinni et al (2020) have identified an overlap of 139 genes among HD, AD, PD and ALS, which were also involved in the response to heat and hypoxia (Ruffini et al, 2020). In this context, modulation of heat shock response geneshas also been proposed to be a potential therapeutic target in neurodegenerative diseases associated with misfolded protein aggregates (Ramos et al, 2018;Gomez-Paredes et al, 2021;Labbadia and Morimoto, 2013).…”