Poster abstracts

Poster number 95 submitted by SungWon Song

ALS astrocytes adopt natural killer properties to kill motor neurons

SungWon Song, Shibi Likhite (Molecular Cellular Developmental Biology, The Ohio State University), Carlos Miranda, Lyndsey Braun, Kathrin Meyer, Laura Ferraiuolo (Center for Gene Therapy, Nationwide Childrens Hospital), Adam K. Bevan, Ashley Frakes (Biomedical Sciences Graduate Program, The Ohio State University), Christopher M. Walker, Brian K. Kaspar (Center for Gene Therapy, Nationwide Childrens Hospital), Kevin D. Foust (Department of Neuroscience, The Ohio State University), Michael J. McConnell (Center for Brain Immunology and Glia, School of Medicine, University of Virginia)

Abstract:
Amyotrophic lateral sclerosis (ALS) is a late onset, fast progressing and always fatal motor neuron (MN) disease. Recently, dramatic reduction of major histocompatibility complex class I (MHCI) in MNs was reported in rapidly progressive ALS mice, suggesting beneficial role of MHCI in preserving MNs during disease. In consistent with previous findings from ALS mice, we observed the substantial reduction of MHCI signals in human MNs in ALS postmortem tissue. Interestingly, in vitro co-culture model of ALS demonstrated that this is mediated by non-cell autonomous effects, specifically by ALS astrocytes.

In ALS, astrocytes have been identified as mediators of MN death. However, the mechanism how ALS astrocytes specifically recognize and kill MNs has remained unknown. We hypothesized that ALS astrocytes discriminate target MNs based on the reduced level of MHCI. Mouse and human ALS astrocytes expressed MHCI inhibitory receptors, which are known to recognize low level of MHCI in target cells and activate killing pathway. Overexpression of MHCI in MNs known to bind to these receptors protected MNs from ALS astrocytes toxicity in vitro and extended survival and delayed the disease progression by 38% in ALS mice.

We extended our studies to determine how astrocytes kill MNs in ALS. It is well known that natural killer (NK) cells utilize two cytolytic proteins, pore forming protein, perforin (PRF1) and cell death-inducing proteases granzyme B (GZMB), which are secreted by reduced MHCI in target cells. Like NK cells, low MHCI in MNs triggered both mouse and human ALS astrocytes to actively release PRF1 and GZMB. Suppression of PRF1 or GZMB expression in these ALS astrocytes resulted in MN protection during in vitro co-culture.

Taken together, our results show that ALS astrocytes specifically display toxicity towards MNs by detecting decreased levels of MHCI and engage a killing mechanism, which is a mechanism reminiscent of the innate immune system. These findings have great implication for ALS research on the aspect of potential therapeutic opportunities.

References:
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Keywords: amyotrophic lateral sclerosis, astrocyte, major histocompatibility complex class 1