Predicting disease specific spinal motor neurons and glia in sporadic ALS

Abstract

Increasing evidence shows that neuroinflammation mediated by activated glia and infiltrated immune cells is involved in the pathogenesis of sporadic amyotrophic lateral sclerosis (sALS). However, the mechanisms of interaction between activated glia and motor neuron degeneration are unclear. To determine the relationship between motor neurons and glial activation in the central nervous system of sALS patients, we applied new cellular interactome bioinformatics tools to transcriptome profiles established from laser captured motor neurons in regions remote from site of onset. We found a disease specific subtype of motor neuron that inversely correlated with survival of sALS patients. Interestingly, two subtypes of motor neurons (motorneuron2 and 3) and two subtypes of microglia/macrophages (microglia/macrophage1 and 2) were unique to sALS patients compared to controls. Increased microglia/macrophage1 correlated with decreased motorneuron2 and increased microglia/macrophage2 correlated with decreased motor neuron3. Increased MHC class II genes correlated with microglia/macrophage1-2. Tissue staining using immunofluorescence confirmed a significant increase of microglia/macrophage expressing MHC class II, suggesting that they were activated. Identified gene pathways and biological changes included apoptosis and protein phosphorylation in motorneuron3 and antigen processing/presentation and immune cell activation in microglia/macrophages in sALS patients. Our findings support the hypothesis that neuro-glia physical interactions are important in pathogenesis, and targeting disease-specific motor neurons and/or glia could be a useful therapy to slow disease progression.