Prion-like spread of protein aggregates in neurodegeneration

Abstract

Protein misfolding is common to most neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Recent work using animal models with intracellular α-synuclein and tau inclusions adds decisively to a growing body of evidence that misfolded protein aggregates can induce a self-perpetuating process that leads to amplification and spreading of pathological protein assemblies. When coupled with the progressive nature of neurodegeneration, recognition of such cell-to-cell aggregate spread suggests a unifying mechanism underlying the pathogenesis of these disorders.

Figure 1.

Scheme summarizing evidence for seeded aggregation and cell-to-cell spreading in animal models of neurodegeneration. The figure depicts the experimental paradigm originally used to replicate infectious prions in mice, which is now used to replicate spreading of misfolded Aβ, α-synuclein, and tau. Protein aggregate containing brain lysates from old sick mice (A) or pure recombinant fibrils aggregated in vitro (B) are introduced in the brains of young asymptomatic mice by injection. It is important to note that some prion-containing lysates (Chandler, 1961) or synthetic prion aggregates (Wang et al., 2010) can transmit disease to wild-type nontransgenic mice, whereas all other aggregates have thus far only been shown to induce aggregation and neuronal dysfunction in transgenic mice expressing the human versions of the respective proteins.