Removing Prion Protein from Human Astrocytes Alters Reactivity and Mitochondria but Not Neuronal Support

Human prion diseases are fatal neurodegenerative conditions driven by the misfolding and aggregation of the cellular prion protein, known as PrP. Because current therapeutic strategies aim to remove PrP from the brain to reduce its availability, researchers have intensively studied the protein’s role in neurons. A new study addresses this gap with a novel human cell model built from astrocytes isolated from dorsal forebrain organoids.

The model differs from a common alternative approach. Astrocytes derived directly from induced pluripotent stem cells tend to be relatively uniform, whereas the organoid-isolated cells used here are more heterogeneous and, according to the authors, better represent the cell morphology seen in the human brain.

Comparing PrP knockout astrocytes with wild-type astrocytes, the researchers found that loss of the protein was associated with increased markers of reactivity and more pro-inflammatory properties. The cells also showed an increased mitochondrial density and impaired mitochondrial function, linking PrP absence to measurable changes in the organelles that supply cellular energy.

Those changes did not translate into harm to neurons, however. The PrP knockout astrocytes did not secrete neurotoxic molecules, and in the study’s in vitro tests they were able to support neurons as well as wild-type astrocytes did. The authors summarize the central takeaway as follows: despite changes in reactivity and mitochondrial function, the absence of PrP does not render human astrocytes neurotoxic or unable to support neuronal function in the laboratory setting.

The result carries weight for therapeutic development. If removing PrP from the brain is the goal of emerging prion disease treatments, the new findings suggest that its loss in astrocytes produces reactivity and mitochondrial changes but not a toxic glial environment, at least under the conditions tested. The work is published in Cellular and Molecular Neurobiology as an open-access original research article, with a version shared early to provide faster access to the peer-reviewed, accepted research; the published version remains subject to further editorial edits before the final Version of Record replaces it.

Subject of Research: The effects of prion protein knockout in a novel human astrocyte model derived from forebrain organoids

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

Article References: Hay, A., Williams, K., Groveman, B., Foliaki, S., Shue, B., & Haigh, C. (2026). Knock-Out of Prion Protein Associated with Reactivity and Mitochondrial Abnormalities in a Novel Human Astrocyte Model. Cellular and Molecular Neurobiology. https://doi.org/10.1007/s10571-026-01824-5

Image Credits: AI Generated

DOI: 10.1007/s10571-026-01824-5

Keywords: prion protein, astrocytes, prion diseases, organoids, mitochondria, reactivity, neuroinflammation, induced pluripotent stem cells, neurodegeneration, cell model, Knock-Out, Prion