Prion-like mechanisms in neurodegenerative diseases

Abstract

Many non-infectious neurodegenerative diseases are associated with the accumulation of fibrillar proteins. These diseases all exhibit features that are reminiscent of those of prionopathies, including phenotypic diversity and the propagation of pathology. Furthermore, emerging studies of amyloid-beta, alpha-synuclein and tau--proteins implicated in common neurodegenerative diseases--suggest that they share key biophysical and biochemical characteristics with prions. Propagation of protein misfolding in these diseases may therefore occur through mechanisms similar to those that underlie prion pathogenesis. If this hypothesis is verified in vivo, it will suggest new therapeutic strategies to block propagation of protein misfolding throughout the brain.

Figure 1. Potential mechanisms for trans-cellular propagation of protein misfolding

(A) Intracellular protein aggregation leads to cell death. This results in release of protein aggregates into the extracellular space, which are subsequently taken up and corrupt protein folding in vulnerable cells. (B) As part of the physiology of a living cell, protein aggregates may be released, potentially via exosomes or exocytosis. This results in protein aggregates in the extracellular space that may be taken up by adjacent cells. This mechanism can account for local propagation of misfolding, along with (A). (C) Aggregates might cross synapses. Release could be due to local degeneration of a synapse, normal synaptic physiology, or as part of an exocytic process as in (B). This mechanism can explain network degeneration in neurodegenerative diseases.

Figure 2. New therapeutic approaches

If trans-cellular propagation of protein misfolding occurs, then new strategies could supplement existing approaches to promote cell survival and block intracellular accumulation of misfolded species. As the cellular mechanisms of aggregate release and uptake are delineated, it may be possible to inhibit these events pharmacologically or genetically. Antibody-based therapies might also be expanded to target protein aggregates that are generated inside a cell and released into the extracellular space.