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

Abstract

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 plateimmobilized 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.

The Toxicity and Polymorphism of β-Amyloid Oligomers

“…However, Aβos bind to PrP c and affect PrP c normal physiological functions in AD brains [ 28 , 29 ]. Aβos can directly interact with PrP c , impair LTP and cause neuritic dystrophy by activating Fyn tyrosine kinase and causing phosphorylation of N -methyl- d -aspartate receptor (NMDAR), but when the expression of PrP c is removed, these adverse effects are deprived [ 30 , 31 , 32 ].…”

Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration

“…Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia (SCA) are the most common neurodegenerative diseases [1]. They are a primary public health problem, affecting tens of millions of people worldwide [2]. Although their complex and endogenous antioxidant defense system [7], plays a key role in neurodegeneration as the brain is characterized by an elevated oxygen consumption, high levels of iron and copper, involved in ROS production, elevated content of polyunsaturated fatty acids, and low antioxidant defenses [1,8].…”

The extent of protein hydration dictates the preference for heterogeneous or homogeneous nucleation generating either parallel or antiparallel β-sheet α-synuclein aggregates

“…In order to compare aggregation kinetics and avoid possible effects of surface material of different sample containers 11 (see Fig. S1), all the aggregation kinetics data shown in this study were performed in hydrophilic PEGylated plates 21,22 , unless otherwise stated. Under these conditions, the aggregation kinetic curves obtained were highly variable ( Fig.…”