Objective: With DNA microarray, we analyze the molecular pathomechanism in sporadic ALS spinal cords with a focus on the function of microglia and astrocytes. We analyzed the microarray data in the cell type specific manner to understand the molecular mechanisms within each cell type of ALS spinal cord.

Background: Glial cells including astrocytes and microglia are reported to be actively involved in motor neuron death in ALS, but the precise mechanisms for the non-cell autonomous neuron death have not been elucidated.

Design/Methods: We profiled using DNA microarray the mRNA expression with cervical spinal cords of 4 sporadic ALS patients and 5 disease-control. To predict the cell type(s) in which each gene was expressed abundantly, we established the cell-type specific transcriptomes using mouse CNS primary culture, then the integrated database was converted to human orthologue. Isolated misregulated genes from microarray was analyzed in terms of glial functions, by using cell-type specific mouse transcriptomes.

Results: We isolated 197 genes which were significantly changed in the spinal cords of ALS patients. We then classified these genes according to the cells that expressed those genes abundantly, and found nearly half of those genes were expressed abundantly in microglia or astrocytes. Furthermore, many of these genes were also changed in ALS mouse models (SOD1G37R Tg mice, SOD1G85R Tg mice). We confirmed that the predicted gene expression pattern was true by immunohistochemistry for several genes with spinal cords of ALS mouse models. Pathway analysis predicted that innate immunity was one of the significantly altered pathways in glial cells.

Conclusion: We could predict the molecular pathomechamism, especially of glia contributing to the non-cell autonomous motor neuronal death of the ALS in the spinal cord that consists of heterogenous cell types.