Meta-analysis of Gene Expression in Neurodegenerative Diseases Reveals Patterns in GABA Synthesis and Heat Stress Pathways

TL;DR

This meta-analysis of RNA-Seq data across Alzheimer's, Parkinson's, and ALS reveals shared alterations in GABA synthesis and heat stress response pathways, highlighting common molecular mechanisms in neurodegenerative diseases.

Contribution

It identifies common gene expression patterns and pathway alterations in neurodegenerative diseases through a system-wide meta-analysis of RNA-Seq data.

Findings

Shared downregulation of GABA synthesis genes GAD1 and GAD2.

Upregulation of heat stress response genes like DNAJB6 and HSP90AA1.

Corroboration of findings with recent literature.

Abstract

Neurodegenerative diseases are characterized as the progressive loss of neural cells, e.g. neurons, glial cells. Ageing, monogenic variations, viral infections, and many other factors are determined and speculated as causes for them. While many individual genes, such as APP for Alzheimer disease and HTT for Huntington disease, and biological pathways are studied for neurodegenerative diseases, system-wide pathogenesis studies are limited. In this study, we carried out a meta-analysis of RNA-Seq studies for three neurodegenerative diseases, namely Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS) to minimize the batch effect derived differences and identify the similarly altered factors among studies. Our main assumption is that these three diseases share some pathological pathway pattern. For this purpose, we downloaded publicly available Alzheimer's disease (84 patients + 33 controls = 117 individuals), Parkinson's disease (28 patients + 43 controls = 71 individuals) and ALS (2 studies: 46 patients + 25 control = 71 individuals) RNA-Seq data from Sequence Read Archive (SRA) database. The significantly differentially expressed genes common to these studies were first identified and analyzed for the patterns in their pathways and variations. Our meta-analysis revealed the shared nature of differential gene expression and mutation load of the cellular heat stress response and GABA synthesis in neurodegenerative diseases. The downregulated GABA synthesis-related genes (e.g. GAD1 and GAD2) and the upregulated cellular heat stress response-related genes (e.g. DNAJB6 and HSP90AA1), in addition to their expression patterns, contain unique variations in samples from patients with neurodegenerative diseases. The significance of genes and pathways we identified in this study corroborated by the recent literature on neurodegenerative diseases.