Differential expression of genes in amyotrophic lateral sclerosis revealed by profiling the post mortem cortex

Abstract

The possible causes of ALS are unknown and multiple biological systems have been implicated. The goal of this study was to use gene expression profiling to evaluate a broad spectrum of systems in ALS. For this study, the medial lip of the human motor cortex and adjacent sensory cortex were collected at autopsy from five ALS patients and three normal individuals. Quantitative filter analysis revealed differential expression of mRNAs normalized to internal standards. A significant difference in expression of 275 genes was found in the ALS motor cortex; of the genes whose expression was changed, 10 were up‐regulated and 265 were down‐regulated. Six of the up‐regulated genes were associated with cell surface activity and two were glutamate receptors; the latter is potentially consistent with the idea of excitotoxicity contributing to neurodegeneration in ALS. Of the down‐regulated genes, the largest number were associated with transcription followed by those involved in antioxidant systems, inflammation, regulation of motor neuron function, lipid metabolism, protease inhibition, and protection against apoptosis including vascular endothelial growth factor. There were no significant differences in gene expression patterns between the sensory and motor cortex in the ALS brains. A total of 10% of the genes identified by microarray were chosen from each of the gene groups for validation by quantitative real time PCR (QRT‐PCR). In order to increase the reliability of our gene array data, newly acquired motor and sensory cortex of ALS and control cases (n = 4 each) were used for validation. Of these, 86.4% changed in the same direction as determined in the microarrays. The gene profile data reported here are consistent with evidence that the ALS brain is characterized by an environment that is permissive for apoptosis, excitotoxicity and abnormal ubiquitination. This gene array study also suggested that a metal imbalance particularly for zinc could exist in ALS. Finally, given the amount of cellular stress that is thought to be part of the pathogenesis in ALS, there was a notable lack of increase in genes required to mount a protective response. This latter observation provides a conceptual framework in which to consider the possibility that ALS could result from a failure to mount adequate protective responses to physiological insults that, left unchecked, could progress to neurodegeneration.

• Oxidative stress
• genomics
• motor cortex
• sensory cortex
• Affymetrix