PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins

• DOI: 10.1007/s00401-019-02114-9
• Publication Date: 2019-12-18T09:04:05Z
• Authors: Grant T. Corbett; Zemin Wang; Wei Hong; Marti Colom-Cadena; Jamie Rose; Meichen Liao; Adhana Asfaw; Tia C. Hall; Lai Ding; Alexandra DeSousa; Matthew P. Frosch; John Collinge; David A. Harris; Michael S. Perkinton; Tara L. Spires-Jones; Tracy L. Young-Pe...; Andrew Billinton; Dominic M. Walsh
• Keywords: Synuclein; Lewy body

Neurodegenerative diseases are an enormous public health problem, affecting tens of millions people worldwide. Nearly all these characterized by oligomerization and fibrillization neuronal proteins, there is great interest in therapeutic targeting aggregates. Here, we show that soluble aggregates α-synuclein tau bind to plate-immobilized PrP vitro on mouse cortical neurons, this binding requires at least one the same N-terminal sites which Aβ bind. Moreover, tau, cause both functional (impairment LTP) structural (neuritic dystrophy) compromise deficits absent when ablated, knocked-down, or neurons pre-treated with anti-PrP blocking antibodies. Using all-human experimental paradigm involving: (1) isogenic iPSC-derived expressing lacking PRNP, (2) aqueous extracts from brains individuals who died Alzheimer's disease, dementia Lewy bodies, Pick's demonstrate Aβ, toxic a manner