Zombosomes are anucleated cell couriers that spread α-synuclein pathology

Astrocytes play a central role in orchestrating the brains microenvironment, but are also tightly connected to neurodegenerative processes. Hence, unraveling astrocytes’ intercellular pathways can give important insight into disease spreading mechanisms. Here we describe a completely new form of actively migrating cellular vehicles that we named zombosomes. Zombosomes shed from astrocytes, but retain their adhesive and motile properties, even though they lack nuclei. Comprehensive analysis of their content revealed that they share protein markers with their parental astrocytes and can be loaded with intact organelles. Importantly, zombosomes act as disease couriers, transferring α-synuclein aggregates from one cell to another, and have the capacity to infiltrate and induce pathology in cerebral organoids. Analysis of human brain sections showed that zombosomes are especially frequent around corpora amyalcea and can carry aggregated α-synuclein. Considering the zombosomes’ content and motility, they propose a likely source of corpora amylacea and the pathological proteins that they harbor. Taken together, our findings represent a new interaction pathway between distant cells through “live” vesicles that when misused, can result in Parkinson’s disease propagation.