Astrocytes expressing mutant hnRNPA1 induce non-cell-autonomous motor neuron death

Abstract

Pathogenic mutation of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is causative to amyotrophic lateral sclerosis (ALS). Neuron death resulting from pathogenic hnRNPA1 may not require its presence across all pertinent cells types, including neurons, glia, and muscles. Rather, the exclusive presence of pathogenic hnRNPA1 in a specific cell type, such as astrocytes, may suffice to substantially alter cellular functions. Consequently, this alteration initiates abnormal interaction within intricate neuron-glia networks, culminating in non-cell-autonomous motor neuron death. To investigate the pivotal role of non-cell-autonomous neuron death in hnRNPA1-associated ALS, we developed transgenic rats overexpressing mutant hnRNPA1 in specifically astrocytes. The confined overexpression of pathogenic hnRNPA1 in astrocytes instigated a sequence of events resulting in motor neuron death and subsequent muscle atrophy. These findings underscore the critical, non-cell-autonomous contribution of astrocytes to hnRNPA1-induced neurodegeneration in ALS, and point toward astrocytic pathways as potential therapeutic targets.