Loss of MHCI exposes motor neurons to astrocyte-mediated toxicity

A report in Nature Medicine sheds new light on astrocyte-mediated toxicity, which is thought to be an important contributor to motor neuron death in amyotrophic lateral sclerosis (ALS). The study demonstrates that astrocytes carrying ALS-related mutations cause downregulation of MHC class I (MHCI) expression on motor neurons, which in turn makes the neurons more susceptible to the toxic effects of the astrocytes.

These findings reconcile two pre-existing lines of evidence. First, astrocytes from individuals with ALS have been shown to be toxic to motor neurons in culture. Second, in the SOD1^G93A mouse model of ALS, elevated MHCI expression on motor neurons is associated with reduced rates of disease progression.

“We have always been interested in understanding the mechanisms underlying the astrocyte–motor neuron interaction,” says Brian Kaspar, who led the new study. “Furthermore, we have been studying immune molecules in the context of glial cell biology in ALS.”

Kaspar's team observed loss of MHCI expression in spinal motor neurons from SOD1^G93A mice and patients with ALS. In addition, wild-type motor neurons that were co-cultured with astrocytes from SOD1^G93A mice exhibited downregulation of MHCI.

astrocyte-conditioned medium induced downregulation of MHCI in motor neurons

Interestingly, SOD1^G93A motor neurons that were cultured in the absence of SOD1^G93A astrocytes expressed near-normal levels of MHCI, and SOD1^G93A astrocyte-conditioned medium induced downregulation of MHCI in motor neurons. Taken together, these findings imply that factors secreted by SOD1^G93A astrocytes were responsible for the loss of MHCI expression.

To explore the relationship between MHCI expression and vulnerability to astrocyte-mediated toxicity, the researchers generated motor neuron lines that overexpressed various MHCI molecules, and they co-cultured these cells with SOD1^G93A astrocytes. H2-K^b overexpression was found to provide complete protection against SOD1^G93A astrocyte-induced toxicity, whereas two other MHCI molecules, H2-D^b and H2-L^d, only provided partial protection.

The team also generated SOD1^G93A mice that overexpressed H2^k or H2^d — the genes that encode H2-K^b and H2-D^b, respectively. Consistent with the in vitro data, overexpression of H2^k, but not H2^d, delayed disease progression and improved motor performance.

“Further work is warranted; for example, what are astrocytes secreting — or not secreting — that has the effect of reducing MHCI presentation on motor neurons?” says Kaspar. Therapeutic strategies for future investigation could include maintenance of MHCI expression on motor neurons, as well as inhibition of astrocyte-induced toxicity.