Glial pathology in amyotrophic lateral sclerosis

Dominant mutations in the Cu/Zn superoxide dismutase (SOD1) gene lead to a familial form of amyotrophic lateral sclerosis (ALS). Although ubiquitous expression of mutant SOD1 provokes progressive, selective motor neuron degeneration in human and rodents due to an acquired toxic property (ies) of the mutant, genetic and chimeric mice studies using SOD1 models indicate that non-neuronal cells play important roles in neurodegeneration through non-cell autonomous mechanism. Recent discovery of TDP-43 protein accumulation as a pathological hallmark of sporadic ALS suggested that the mechanisms of neurodegeneration in SOD1-linked familial ALS and sporadic ALS may be distinct. This prompted us to test whether SOD1-ALS and sporadic ALS share the common disease mechanisms in glial cells. To address this question, we have compared gene expression profile of spinal cords of SOD1 mice and sporadic ALS patients by establishing the cell-type specific transcriptome. Significant overlap of misregulated genes enriched in microglia was observed in sporadic ALS and SOD1 mouse models. The pathway analysis indicated the innate immune system, NF-kappaB signaling, and caspase-interleukin cascade that were misregulated in glial cells, suggesting these pathways may be the potential targets for disease modifying therapy of ALS.