Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases

Abstract

IntroductionNeurodegenerative diseases share common pathologic features including neuroinflammation, mitochondrial dysfunction and protein aggregation, suggesting common underlying mechanisms of neurodegeneration. We undertook a meta-analysis of public gene expression data for neurodegenerative diseases to identify a common transcriptional signature of neurodegeneration.ResultsUsing 1,270 post-mortem central nervous system tissue samples from 13 patient cohorts covering four neurodegenerative diseases, we identified 243 differentially expressed genes, which were similarly dysregulated in 15 additional patient cohorts of 205 samples including seven neurodegenerative diseases. This gene signature correlated with histologic disease severity. Metallothioneins featured prominently among differentially expressed genes, and functional pathway analysis identified specific convergent themes of dysregulation. MetaCore network analyses revealed various novel candidate hub genes (e.g. STAU2). Genes associated with M1-polarized macrophages and reactive astrocytes were strongly enriched in the meta-analysis data. Evaluation of genes enriched in neurons revealed 70 down-regulated genes, over half not previously associated with neurodegeneration. Comparison with aging brain data (3 patient cohorts, 221 samples) revealed 53 of these to be unique to neurodegenerative disease, many of which are strong candidates to be important in neuropathogenesis (e.g. NDN, NAP1L2). ENCODE ChIP-seq analysis predicted common upstream transcriptional regulators not associated with normal aging (REST, RBBP5, SIN3A, SP2, YY1, ZNF143, IKZF1). Finally, we removed genes common to neurodegeneration from disease-specific gene signatures, revealing uniquely robust immune response and JAK-STAT signaling in amyotrophic lateral sclerosis.ConclusionsOur results implicate pervasive bioenergetic deficits, M1-type microglial activation and gliosis as unifying themes of neurodegeneration, and identify numerous novel genes associated with neurodegenerative processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0093-y) contains supplementary material, which is available to authorized users.

Genes associated with body weight gain and feed intake identified by meta-analysis of the mesenteric fat from crossbred beef steers

“…One way to isolate the genes that contribute to phenotype, regardless of environment, is to evaluate several cohorts of animals and analyze the data using a meta-analysis [5]. These types of analyses are more likely to produce valid results in independent datasets [6][7][8].…”

The Stress-Inducible Protein DRR1 Exerts Distinct Effects on Actin Dynamics

“…Lately, DRR1 has been associated to several brain disorders. Gene expression analyses indicated altered expression of DRR1 in neurodegenerative diseases as well as in bipolar disorder, autism spectrum disorder, and schizophrenia, presumably indicating an aberrant adaptation to chronic stress [40,41,42,43,44,45,46].…”

Expression and glucocorticoid-dependent regulation of the stress-inducible protein DRR1 in the mouse adult brain

“…The stress-inducible gene down-regulated in renal cell carcinoma 1 (DRR1, also known as TU3A and Fam107A) was initially identified as a putative tumor suppressor gene in renal cell carcinoma (Yamato et al 2000; Wang et al 2000), then as unique gene increased in both psychiatric and neurodegenerative disorders (Shao and Vawter 2008; Li et al 2014; Shin et al 2016) and recently pointed as a novel molecular player promoting stress resilience (Masana et al 2014, 2015; van der Kooij et al 2016), supporting the involvement of DRR1 in modulating neuronal function under pathophysiological conditions. Interestingly, DRR1 is an actin-interacting protein and during recent years, neuronal actin dysfunction has been suggested as a potential shared pathological mechanism in neurodevelopmental disorders (van der Kooij et al 2016; Yan et al 2016).…”