Mini-Brain Model Developed for Human Prion Disease

Recapitulation of in vivo conditions is the ultimate goal of model systems for the study of disease states, and in recent years scientists have made considerable strides with 3D tissue culture systems that are producing mini-organs, often referred to as organoids. Now, investigators at the NIH have used human skin cells to create what they believe is the first cerebral organoid system, or “mini-brain,” for studying sporadic a sporadic prion disorder known as Creutzfeldt-Jakob disease (CJD). Findings from this new study were published recently in Acta Neuropathologica Communications through an article entitled “Sporadic Creutzfeldt-Jakob disease prion infection of human cerebral organoids.”

CJD is a fatal neurodegenerative brain disease of humans caused by an infectious prion protein and affects about 1 in 1 million people. The researchers, from NIH’s National Institute of Allergy and Infectious Diseases (NIAID), hope their human organoid model will enable them to evaluate potential therapeutics for CJD and provide greater detail about human prion disease subtypes than the rodent and nonhuman primate models currently in use.

“To determine whether organoids could be used to reproduce human prion infection and pathogenesis, we inoculated organoids with two sporadic Creutzfeldt-Jakob Disease prion subtypes,” the authors wrote. “Organoids showed uptake, followed by clearance, of the infectious inoculum. Subsequent re-emergence of prion self-seeding activity indicated de novo propagation. Organoid health assays, prion titer, prion protein electrophoretic mobility, and immunohistochemistry demonstrated inoculum-specific differences.”

Human cerebral organoids are small balls of human brain cells ranging in size from a poppy seed to a small pea. Their organization, structure, and electrical signaling are similar to brain tissue. Because these cerebral organoids can survive in a controlled environment for months, nervous system diseases can be studied over time. Cerebral organoids have been used as models to study Zika virus infection, Alzheimer’s disease, and Down syndrome.

In the current study, the researchers discovered how to infect five-month-old cerebral organoids with prions using samples from two patients who died of two different CJD subtypes, MV1, and MV2. The infection took about one month to confirm, and the scientists monitored the organoids for changes in health indicators, such as metabolism, for more than six months. By the end of the study, the scientists observed that seeding activity, an indication of infectious prion propagation, was present in all organoids exposed to the CJD samples. However, seeding was greater in organoids infected with the MV2 sample than the MV1 sample. They also reported that the MV1-infected organoids showed more damage than the MV2-infected organoids.

Additionally, the research team noted other differences between how the MV1 and MV2 infections evolved in the organoids. They plan to investigate further those differences in hopes of identifying how different subtypes of CJD affect brain cells. Ultimately, they hope to learn how to prevent cell damage and to restore the function of cells damaged by prion infection. The new system also provides opportunities to test potential therapeutics for CJD in a tissue model that mimics the human brain.

“Our study shows, for the first time, that cerebral organoids can model aspects of human prion disease and thus offer a powerful system for investigating different human prion subtype pathologies and testing putative therapeutics,” the authors concluded.