Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: Implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is the most common motor neu-ron disease and is still incurable. The mechanisms leading to theselective motor neuron vulnerability are still not known. The inter-play between motor neurons and astrocytes is crucial in the out-come of the disease. We show that mutant copper-zinc superoxidedismutase (SOD1) overexpression in primary astrocyte cultures isassociated with decreased levels of proteins involved in secretorypathways. This is linked to a general reduction of total secretedproteins, except for specific enrichment in a number of proteins inthe media, such as mutant SOD1 and valosin-containing protein(VCP)/p97. Because there was also an increase in exosome release,we can deduce that astrocytes expressing mutant SOD1 activateunconventional secretory pathways, possibly as a protective mech-anism. This may help limit the formation of intracellular aggre-gates and overcome mutant SOD1 toxicity. We also found thatastrocyte-derived exosomes efficiently transfer mutant SOD1 tospinal neurons and induce selective motor neuron death. We con-clude that the expression of mutant SOD1 has a substantial impacton astrocyte protein secretion pathways, contributing to motorneuron pathology and disease spread.