Journal Article

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

Asfaw, Adhana, Young-Pearse, Tracy L., Corbett, Grant T., Hong, Wei, Wang, Zemin, Perkinton, Michael S., DeSousa, Alexandra, Hall, Tia C., Rose, Jamie, Frosch, Matthew P., Spires-Jones, Tara L., Ding, Lai, Collinge, John, Walsh, Dominic M., Liao, Meichen, Harris, David A., Colom-Cadena, Marti, Billinton, Andrew

2020

Overview

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

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V
• Subject: alpha-Synuclein - metabolism / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Animals / Antibodies / Blocking antibodies / Brain / Brain - metabolism / Dementia disorders / Disease / Dystrophy / Fibrillogenesis / Health aspects / Humans / Lewy bodies / Medicine / Medicine & Public Health / Mice / Nervous system diseases / Neurodegeneration / Neurodegenerative diseases / Neurodegenerative Diseases - metabolism / Neurons / Neurons - metabolism / Neurosciences / Oligomerization / Oligomers / Original Paper / Pathology / Prion protein / Prions - metabolism / Protein Binding / Proteins / Public health / Synuclein / Tau protein / tau Proteins - metabolism / Therapeutic targets / Toxicity / Viral antibodies