Gene expression signatures in motor neurone disease fibroblasts reveal dysregulation of metabolism, hypoxia-response and RNA processing functions

Rohini Raman, Scott P. Allen, Emily F. Goodall, Shelley Kramer, Lize Linde Ponger, Paul R. Heath, Marta Milo, Hannah C. Hollinger, Theresa Walsh, J. Robin Highley, Simon Olpin, Christopher J. Mcdermott, Pamela J. Shaw, Janine Kirby

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)


Aims: Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are two syndromic variants within the motor neurone disease spectrum. As PLS and most ALS cases are sporadic (SALS), this limits the availability of cellular models for investigating pathogenic mechanisms and therapeutic targets. The aim of this study was to use gene expression profiling to evaluate fibroblasts as cellular models for SALS and PLS, to establish whether dysregulated biological processes recapitulate those seen in the central nervous system and to elucidate pathways that distinguish the clinically defined variants of SALS and PLS. Methods: Microarray analysis was performed on fibroblast RNA and differentially expressed genes identified. Genes in enriched biological pathways were validated by quantitative PCR and functional assays performed to establish the effect of altered RNA levels on the cellular processes. Results: Gene expression profiling demonstrated that whilst there were many differentially expressed genes in common between SALS and PLS fibroblasts, there were many more expressed specifically in the SALS fibroblasts, including those involved in RNA processing and the stress response. Functional analysis of the fibroblasts confirmed a significant decrease in miRNA production and a reduced response to hypoxia in SALS fibroblasts. Furthermore, metabolic gene changes seen in SALS, many of which were also evident in PLS fibroblasts, resulted in dysfunctional cellular respiration. Conclusions: The data demonstrate that fibroblasts can act as cellular models for ALS and PLS, by establishing the transcriptional changes in known pathogenic pathways that confer subsequent functional effects and potentially highlight targets for therapeutic intervention.

Original languageEnglish
Pages (from-to)201-226
Number of pages26
JournalNeuropathology and Applied Neurobiology
Issue number2
Publication statusPublished - 1 Feb 2015


  • Amyotrophic lateral sclerosis
  • Cell models
  • Fibroblasts
  • Hypoxia response
  • Microarray
  • MicroRNA
  • Primary lateral sclerosis


Dive into the research topics of 'Gene expression signatures in motor neurone disease fibroblasts reveal dysregulation of metabolism, hypoxia-response and RNA processing functions'. Together they form a unique fingerprint.

Cite this