Infecting human brain organoids with FFI or sCJD preserves prion traits regardless of host genotype

Area of Science:

• Neuroscience
• Prion Biology
• Molecular Genetics

Background:

• Prion diseases are fatal neurodegenerative disorders.
• These diseases stem from misfolded prion proteins (PrP).
• Specific mutations, like D178N, cause genetic prion diseases such as Fatal Familial Insomnia (FFI).

Purpose of the Study:

• To investigate the infectivity of sporadic Creutzfeldt-Jakob Disease (sCJD) and FFI prions in human cerebral organoids.
• To determine if host genotype (D178N mutation) influences prion disease susceptibility in vitro.
• To understand the fundamental mechanisms of prion propagation and host-pathogen interactions.

Main Methods:

• Inoculation of human cerebral organoids with sCJD and FFI prions.
• Culturing and monitoring of infected organoids.
• Analysis of prion infection and propagation within the organoid model.

Main Results:

• Both sCJD and FFI prions successfully infected human cerebral organoids.
• Infection occurred regardless of the presence or absence of the D178N mutation in the organoid's PrP gene.
• The genotype of the host organoid did not dictate the susceptibility or outcome of prion infection.

Conclusions:

• Human cerebral organoids serve as a viable model for studying prion diseases.
• Prion infectivity is determined by the prion strain itself, not the host's genetic background.
• This finding has implications for understanding prion disease pathogenesis and developing therapeutic strategies.