Figure 1.

The relationship between proteostasis and prion-like protein propagation. (A) The proteostasis network (green objects) is composed of molecular chaperone proteins, degradation pathways (proteasomal and autophagic), and the trafficking of proteins. Chaperones act to protect vulnerable proteins from becoming misfolded and aggregating, potentially through the amyloid pathway (blue). During seed/aggregate formation, proteins vulnerable to amyloid aggregation can form polymorphic assemblies through template-directed growth, eventually, elicit different biological and pathological effects dependent on the polymorphic assembly (strain). Amyloid assemblies are thought to propagate from cell-to-cell through exocytosis in vesicles and exosomes, through membrane breakages, macropinocytosis, and tunneling nanotubes. Once an amyloid assembly has been transferred to a naive cell, replication continues as the amyloid assemblies can now recruit vulnerable protein within this cell. (B) In vitro experiments have shown that amyloid formation can be augmented via changes in environmental conditions or mutations (red) in substrate proteins to become more aggressive. Likewise, the addition of molecular chaperones and/or therapeutics (green), such as small molecules or antibodies, can suppress amyloid aggregation. (C) Amyloid aggregation in humans is a stochastic process, occurring over long time scales and, in simplistic terms, is an interplay of proteostasis capacity (green) and protein aggregation propensity (blue). Mutations and/or environmental features can result in both aggressive aggregation and/or a lower proteostasis capacity, ultimately resulting in earlier disease onset in affected individuals.