A multi-parametric imaging assay of prion-induced toxicity

Identification: Reilly, Madeleine


A multi-parametric imaging assay of prion-induced toxicity
Reilly M, Benilova I, Jat P & Collinge J
Department of Neurodegenerative Disease and MRC Prion Unit, UCL Institute of Neurology
Prion diseases involve the conversion of the cellular prion protein (PrPC) to disease associated misfolded isoforms of varying chemistry and structure. Neuropathology relates to a subset of these isoforms, deemed PrP-lethal (PrPL). PrPtoxicity is thought to be mediated through PrPC, however, to characterise and elucidate the exact mechanism of action of PrPL, a robust in vitro assay of prion-induced toxicity was developed. The assay quantitatively measures multiple parameters of prion-induced toxicity in primary neuronal cultures using high throughput imaging and analysis. Toxicity measurements include pyknosis, neuronal loss, neurite fragmentation and dendritic spine atrophy. The read-outs require PrPexpression in cells and importantly distinguish toxicity of homogenates prepared from brains collected from mice culled at different stages of prion disease. The assay provides a platform to understand the toxic signalling pathways that lead to neuronal death in prion disease, identify therapeutic targets and screen therapeutic candidates, to learn more about PrPC itself and toxic signalling mechanisms in other neurodegenerative diseases.


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