Peer-review started: October 1, 2014
First decision: October 28, 2014
Revised: November 21, 2014
Accepted: December 3, 2014
Article in press: December 10, 2014
Published online: December 28, 2014
Processing time: 86 Days and 16 Hours
Neurodegenerative pathology can be seeded by introduction of misfolded proteins and peptides into the nervous system. Models of Alzheimer’s disease (AD) and Parkinson’s disease (PD) have both demonstrated susceptibility to this seeding mechanism, emphasizing the role of misfolded conformations of disease-specific proteins and peptides in disease progression. Thinking of the amyloidogenic amyloid-beta peptide (Aβ) and alpha-synuclein (α-syn), of AD and PD, respectively, as prionoids requires a comparison of these molecules and the mechanisms underlying the progression of disease. Aβ and α-syn, despite their size differences, are both natively unstructured and misfold into β-structured conformers. Additionally, several studies implicate the significant role of membrane interactions, such as those with lipid rafts in the plasma membrane, in mediating protein aggregation and transfer of Aβ and α-syn between cells that may be common to both AD and PD. Examination of inter-neuronal transfer of proteins/peptides provides evidence into the core mechanism of neuropathological propagation. Specifically, uptake of aggregates likely occurs by the endocytic pathway, possibly in response to their formation of membrane pores via a mechanism shared with pore-forming toxins. Failure of cellular clearance machinery to degrade misfolded proteins favours their release into the extracellular space, where they can be taken up by directly connected, nearby neurons. Although similarities between AD and PD are frequent and include mechanistically similar transfer processes, what differentiates these diseases, in terms of temporal and spatial patterns of propagation, may be in part due to the differing kinetics of protein misfolding. Several examples of animal models demonstrating seeding and propagation by exogenous treatment with Aβ and α-syn highlight the importance of both the environment in which these seeds are formed as well as the environment into which the seeds are propagated. Although these studies suggest potent seeding effects by both Aβ and α-syn, they emphasize the need for future studies to thoroughly characterize “seeds” as well as analyze changes in the nervous system in response to exogenous insults.
Core tip: The disease-specific proteins of Alzheimer’s and Parkinson’s disease show many similarities as prion-like seeds in the brain. In addition to sharing structural features as misfolded proteins, the interactions and mechanisms that underlie the propagation of these proteins may also be shared, hijacking natural cellular responses in ways not unlike those of pore-forming toxins. Differences in temporal and spatial patterns of disease progression stems from the existence of conformational variants. Misfolded proteins that can be generated in vitro, can seed widespread pathology in non-transgenic animal models and question our understanding of disease progression in neurodegenerative diseases.