Active roles of glial cells in neurodegenrative disease

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, the distinct roles of mutant toxicity within motor neurons and non-neuronal cells are recently established by our cell-type specific gene ablation from mutant SOD1 mice. The toxicity(ies) within astrocytes and microglia accelerates disease progression, indicating that glial cells contribute to non-cell autonomous neurodegeneration. Misregulated genes within glial cells that we isolated from symptomatic mutant SOD1 mice indicated the involvement of innate immune system. The inhibition of innate immune pathway in SOD1 mice significantly accelerated disease progression. These results indicate the active role of glial cells in modifying disease progression in ALS models.