Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases

Matthew D. Li, Terence Burns, Alexander A. Morgan, Purvesh Khatri

Research output: Contribution to journalReview article

39 Scopus citations

Abstract

Introduction: Neurodegenerative 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. Results: Using 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. Conclusions: Our 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.

Original languageEnglish (US)
Article number93
JournalActa neuropathologica communications
Volume2
Issue number1
DOIs
StatePublished - Jan 27 2014
Externally publishedYes

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Keywords

  • Aging
  • Biomarkers
  • Meta-analysis
  • Neurodegeneration
  • Therapeutic targets
  • Transcriptome

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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