Gene expression profiling in ALS: past, present and future
published: July 21, 2017, recorded: May 2017, views: 0
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Gene expression profiling has come a long way since the term was first widely used in the mid to late 1990’s. With the advent of microarrays allowing the expression levels of increasing numbers of genes to be quantified, gene expression profiling, microarray analysis and transcriptomics have become frequently used terms associated with sampling RNA from multiple different tissue types. The results of these studies have been used to investigate disease mechanisms, monitor progression of disease and identify specific genes or gene signatures which could be used as diagnostic or prognostic biomarkers. Within the field of ALS, researchers have moved from using pooled spinal cord homogenates, to ensure they had sufficient material, through to isolating individual cell types from post-mortem cases and utilising peripheral tissues to determine biomarkers of disease and progression or stratification of patients. Gene expression profiling has been a key methodology used in Sheffield and we initially used it to investigate disease mechanisms associated with mutant SOD1. We were the first to demonstrate the disruption of the NRF2 signalling pathway in a cellular model of SOD1-related ALS, thereby establishing this as a potential therapeutic target which others demonstrated was more widely applicable to other forms of ALS. Several groups, including ourselves have now identified drugs targeting this pathway and it remains a viable target for therapeutic intervention. As knowledge of the genome and transcriptome increased, microarrays evolved to sample not only gene-level expression but that of individual exons, allowing alternatively spliced transcripts to be detected; a timely development given the emerging role of RNA metabolism as a key pathogenic mechanism in ALS. We have demonstrated the disruption of splicing in TARDBP and C9orf72-related ALS, as well as in sporadic ALS cases. Transcriptomics has also expanded from sampling protein coding genes to non-coding transcripts such as miRNAs, which have the potential not only to act as more stable biomarkers, but also to regulate translation, and in themselves be used a therapeutic agents against specific targets. With RNA-sequencing now becoming more affordable and with the advantages of identifying novel transcripts and detecting a greater range of expression levels, the future for gene expression profiling includes focusing on transcripts in specific cellular compartments, being an integral part of clinical trials and perhaps even a standard part of diagnostic procedures and therapeutic decisions.
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