**8. Results from use of human peripheral tissue**

Gene expression profiling has been conducted on blood and fibroblasts from ALS patients (Highley et al 2011; Saris et al 2009; Zhang et al 2011). Microarray analysis of SALS and control blood samples was followed by hierarchical clustering of all genes found to be significantly expressed in all samples after normalisation (Saris et al 2009). The method identified five clusters; two of which were able to differentiate between ALS and control samples. These clusters were replicated in a further two cohorts of patients and controls, demonstrating that such an analysis, which takes into account the interdependence of gene expression, is a means of reducing the false negative rate when subsequently detecting differential gene expression. This work also provided evidence that peripheral blood is a valuable medium for studying ALS. In addition, there was a correlation with the CNS tissue studies, as the blood in ALS patients showed a decrease in genes associated with protein processing and RNA post-transcriptional modification, as well as increases in genes associated with inflammation.

A more recent study performed gene expression profiling on peripheral blood mononuclear cells from patients with SALS (Zhang et al 2011). These cells showed an up-regulation of genes associated with immune activation in response to lipopolysaccharide (LPS), which correlated with an elevation of plasma LPS. Unfortunately, no correlation between expression of these genes and disease progression was provided.

Transcriptional profiles of fibroblasts from patients with SALS, FALS and controls have been shown to be informative in distinguishing the different genetic variants from each other, as well as from SALS patients, by their gene expression profiles and specifically the level of alternative splicing (Highley et al 2011). The FALS samples were derived from patients with mutations in *SOD1* and *TARDBP*. Using microarrays which interrogate every exon of every gene, it was demonstrated that there was a significant amount of aberrant splicing in the samples with a *TARDBP* mutation which was replicated to a lesser degree in the SALS samples and virtually absent in the samples with a *SOD1* mutation (Figure 3). In support of this, other work has identified aberrant splicing in cell and animal models with depletion of TDP-43 (Polymenidou et al 2011; Tollervey et al 2011).
