Knock-Out of Prion Protein Associated with Reactivity and Mitochondrial Abnormalities in a Novel Human Astrocyte Model

Abstract

Human prion diseases are fatal neurodegenerative diseases caused by misfolding and aggregation of the cellular prion protein, PrP. Current therapeutic avenues focus on the removal of PrP to decrease its availability in the brain. Numerous studies have investigated the role of neuronal PrP, but few have focused on PrP in astrocytes. Here we present a novel human cell model using astrocytes isolated from dorsal forebrain organoids. These cells are more heterogenous than astrocytes that are directly differentiated from induced pluripotent stem cells and better represent cell morphology in the human brain. Compared to wild-type astrocytes, PrP knockout astrocytes had increased markers of reactivity and more pro-inflammatory properties. They had an increased mitochondrial density and impaired mitochondrial function. However, PrP knockout astrocytes did not secrete neurotoxic molecules and were able to support neurons as well as wild-type astrocytes. These findings show that, despite changes in reactivity and mitochondrial function, absence of PrP does not render human astrocytes neurotoxic or unable to support neuronal function in vitro.