**6.1 Gene expression profiling of mixed cell type CNS samples**

Microarray analysis of whole spinal cord homogenates from ALS mouse models have been performed by several research groups in order to obtain a global view of changes in the CNS prior to and during disease. Results from SOD1G93A mice have shown that inflammation, apoptosis and adaptive responses to metal ion dysregulation are the main pathways activated in both pre-symptomatic mice and during the disease process (Olsen et al 2001; Yoshihara et al 2002) (Figure 2). Analysis of the SOD1L126delTT transgenic mouse, which results in a truncated SOD1 protein, also showed pre-symptomatic changes related to the reactive gliosis which is occurring in the spinal cord (Fukada et al 2007).

Recently, transgenic mice carrying mutant TDP-43 have also contributed to better understanding the different mechanisms involved in ALS. Transgenic mice induced to

stress, whilst genes involved in the ubiquitin-proteasome system and cytokines were increased following excitotoxicity (Figure 1). Several of these pathways have already been implicated as playing a pathogenic role in ALS and add further support to the idea that the

Fig. 1. Summary of prominent pathways arising from GEP of Cellular Models. Important changes in the transcriptome have been highlighted by green labels; yellow stars indicate

Microarray analysis of whole spinal cord homogenates from ALS mouse models have been performed by several research groups in order to obtain a global view of changes in the CNS prior to and during disease. Results from SOD1G93A mice have shown that inflammation, apoptosis and adaptive responses to metal ion dysregulation are the main pathways activated in both pre-symptomatic mice and during the disease process (Olsen et al 2001; Yoshihara et al 2002) (Figure 2). Analysis of the SOD1L126delTT transgenic mouse, which results in a truncated SOD1 protein, also showed pre-symptomatic changes related to the

Recently, transgenic mice carrying mutant TDP-43 have also contributed to better understanding the different mechanisms involved in ALS. Transgenic mice induced to

up-regulation, red stars indicate down-regulation. Blue squares outline functional consequences of changes in the transcriptome. Further details are discussed in the text.

**6. Results from use of animal models of ALS** 

**6.1 Gene expression profiling of mixed cell type CNS samples** 

reactive gliosis which is occurring in the spinal cord (Fukada et al 2007).

proposed disease mechanisms are mutually compatible.

express human TDP-43 without the nuclear localization signal (hTDP43-delNLS) developed signs of motor spasticity, neurone loss in forebrain regions and corticospinal tract degeneration (Igaz et al 2011). Microarray analysis of hTDP43-delNLS expression in the cortex of mutant mice, following 2 weeks induction of the mutant protein, detected dramatic changes in gene expression, with the most enriched pathway being chromatin assembly (Figure 2). Interestingly, after only 2 weeks of hTDP43-delNLS induction, markers of inflammation and neuronal loss were unchanged.

Fig. 2. Summary of prominent pathways arising from GEP of Animal Models. Important changes in the transcriptome have been highlighted by green labels; yellow stars indicate up-regulation, red stars indicate down-regulation. Blue squares outline functional consequences of changes in the transcriptome. Further details are discussed in the text.

Although these studies have greatly contributed to present knowledge on the transcriptional changes occurring in ALS, the analysis of a mixed cell population within the CNS has several disadvantages. This kind of approach does not identify which cell population is responsible for the transcriptional changes observed and only detects those transcripts most highly differentially expressed, with subtle but potential pivotal gene expression changes masked as well as changes in genes differentially expressed in one cell type, but not in others.
