Sporadic Creutzfeldt-Jakob disease prion infection of human cerebral organoids

Abstract

For the transmissible, neurogenerative family of prion diseases, few human models of infection exist and none represent structured neuronal tissue. Human cerebral organoids are self-organizing, three-dimensional brain tissues that can be grown from induced pluripotent stem cells. Organoids can model aspects of neurodegeneration in Alzheimer’s Disease and Down’s Syndrome, reproducing tau hyperphosphorylation and amyloid plaque pathology. 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. 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. 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. Electronic supplementary material The online version of this article (10.1186/s40478-019-0742-2) contains supplementary material, which is available to authorized users.

Use of 3D Organoids as a Model to Study Idiopathic Form of Parkinson’s Disease

“…Sci. 2020, 21, 694 2 of 13 epilepsy [10], Creutzfeldt-Jakob disease [11] and neuronal ceroid lipofuscinosis [12]. iPSCs also opened up the possibility of studying diseases with unknown pathogenesis.…”

“…These organoids can be generated from iPSCs that are derived from patients, which creates an opportunity for disease modeling, studies on the development and progression of disease, as well as for drug testing. Several studies on brain pathologies have already involved iPSCs derived organoids [8,11,12]. Thus, the 3D model of PD is an excellent tool for studying the pathomechanisms of this disease [18].…”

An astrocyte cell line that differentially propagates murine prions

“…Non-neuronal cell lines were also very instrumental (29,30). Of note, with a few exceptions, such cell line models do not show side effects as would be expected from prion pathogenesis in vivo (31,32), an issue that can be better addressed in primary cells (33), cerebral organoids (34), and slice culture models (35). There was a shortage of glia cell models, with ovine microglia cells for propagation of sheep prions (36) and human stem cell-derived astrocytes replicating even human prions (37,38).…”

Prion infection, transmission, and cytopathology modeled in a low-biohazard human cell line

“…Currently, there are only three reports of human cellular models for prion infection and propagation (Ladogana et al, 1995;Krejciova et al, 2017;Groveman et al, 2019). However, the culture and maintenance of these models are costly, extremely laborious and have limited scalability.…”