Integrated Organotypic Slice Cultures and RT-QuIC (OSCAR) Assay: Implications for Translational Discovery in Protein Misfolding Diseases

• Published in: Scientific reports Vol. 7; no. 1; p. 43155
• Main Authors: Kondru, Naveen, Manne, Sireesha, Greenlee, Justin, West Greenlee, Heather, Anantharam, Vellareddy, Halbur, Patrick, Kanthasamy, Arthi, Kanthasamy, Anumantha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.02.2017; Nature Publishing Group
• Subjects: 13; 14/19; 14/63; 631/378/1689; 631/378/1689/364; Animals; Biological activity; Brain - pathology; Diagnostic Tests, Routine - methods; Disease Models, Animal; Humanities and Social Sciences; Mass Screening - methods; Mice, Inbred C57BL; multidisciplinary; Neurodegenerative diseases; Neurotoxicity; Prion Diseases - diagnosis; Prion Diseases - pathology; Prion protein; Prions; Protein folding; Protein interaction; Protein seeding; Proteins; Science; Tau protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep43155

Protein misfolding is a key pathological event in neurodegenerative diseases like prion diseases, synucleinopathies, and tauopathies that are collectively termed protein misfolding disorders. Prions are a prototypic model to study protein aggregation biology and therapeutic development. Attempts to develop anti-prion therapeutics have been impeded by the lack of screening models that faithfully replicate prion diseases and the lack of rapid, sensitive biological screening systems. Therefore, a sensitive model encompassing prion replication and neurotoxicity would be indispensable to the pursuit of intervention strategies. We present an ultra-sensitive screening system coupled to an ex vivo prion organotypic slice culture model to rapidly advance rationale-based high-throughput therapeutic strategies. This hybrid O rganotypic S lice C ulture A ssay coupled with R T-QuIC (OSCAR) permits sensitive, specific and quantitative detection of prions from an infectious slice culture model on a reduced time scale. We demonstrate that the anti-prion activity of test compounds can be readily resolved based on the power and kinetics of seeding activity in the OSCAR screening platform and that the prions generated in slice cultures are biologically active. Collectively, our results imply that OSCAR is a robust model of prion diseases that offers a promising platform for understanding prion proteinopathies and advancing anti-prion therapeutics.