Prion-like disorders: blurring the divide between transmissibility and infectivity

Abstract

Prions are proteins that access self-templating amyloid forms, which confer phenotypic changes that can spread from individual to individual within or between species. These infectious phenotypes can be beneficial, as with yeast prions, or deleterious, as with mammalian prions that transmit spongiform encephalopathies. However, the ability to form self-templating amyloid is not unique to prion proteins. Diverse polypeptides that tend to populate intrinsically unfolded states also form self-templating amyloid conformers that are associated with devastating neurodegenerative disorders. Moreover, two RNA-binding proteins, FUS and TDP-43, which form cytoplasmic aggregates in amyotrophic lateral sclerosis, harbor a 'prion domain' similar to those found in several yeast prion proteins. Can these proteins and the neurodegenerative diseases to which they are linked become 'infectious' too? Here, we highlight advances that define the transmissibility of amyloid forms connected with Alzheimer's disease, Parkinson's disease and Huntington's disease. Collectively, these findings suggest that amyloid conformers can spread from cell to cell within the brains of afflicted individuals, thereby spreading the specific neurodegenerative phenotypes distinctive to the protein being converted to amyloid. Importantly, this transmissibility mandates a re-evaluation of emerging neuronal graft and stem-cell therapies. In this Commentary, we suggest how these treatments might be optimized to overcome the transmissible conformers that confer neurodegeneration.

Fig. 1.

Prion seeding, strain and fragmentation phenomena. (A) Prions are proteins that exist in several alternative conformations. The first is the native state, depicted by a purple circle. Prion proteins can also exist in numerous distinct self-templating amyloid forms or ‘strains’, depicted by distinct blue polymers. Amyloid forms capture and convert native conformers to the self-templating form at their ends. Typically, this capture and conversion process requires native conformers to exist in a transiently unfolded state or to possess an intrinsically unfolded domain. (B) Amplification of conformational replication is achieved by the fragmentation of amyloid forms to liberate new ends. Fragmentation also allows the dissemination of infectious material. Fibers can fragment spontaneously (Smith et al., 2006), or fragmentation can be catalyzed by cellular factors, such as Hsp104 in yeast (Shorter and Lindquist, 2004). Typically, different strains fragment at different rates. More frangible strains tend to be more potent prions because they expose more fiber ends (the active sites of conformational replication) per unit mass and therefore convert monomers more rapidly (Colby et al., 2009; Tanaka et al., 2006). Indeed, one possible explanation for the reason all self-templating amyloid conformers are not prions is that some strains do not fragment readily enough to sufficiently amplify conformational replication (Salnikova et al., 2005). Thus, a gradient of forms with increasing frangibility can be envisioned, with prions and amyloids existing at opposite ends of the spectrum.

Fig. 2.

Putative prion domains in FUS and TDP-43. (A) Prion domain prediction for Ure2, a known yeast prion protein. The lower part of the panel shows the primary sequence of Ure2, with the predicted prion domain highlighted in red. In accord with experimental data (Masison and Wickner, 1995), the algorithm successfully identifies amino acids 1-89 as the prion domain. The top panel shows the probability of each residue belonging to the Hidden Markov Model state prion domain or ‘background’; the tracks ‘MAP’ and ‘Vit’ illustrate the Maximum a Posteriori and the Viterbi parses of the protein into these two states (for details, see Alberti et al., 2009; this article contains similar plots for 179 yeast proteins in the supplement). The middle panel shows sliding averages over a window of width 51 of net charge (pink), hydropathy (blue) and predicted disorder (gray) (Prilusky et al., 2005), along with a sliding average based on the prion domain amino acid propensities (red). (B) Prion domain prediction for FUS. (C) Prion domain prediction for TDP-43. (D) Domain architecture of FUS. FUS harbors an N-terminal S,Y,Q,G-rich domain (green), followed by a G-rich domain (purple), an RNA-recognition motif (RRM; blue) and two RGG-rich domains (cyan) that surround a zinc-finger domain (yellow). The predicted prion domain encompasses the S,Y,Q,G-rich domain and a portion of the G-rich domain. (E) Domain architecture of TDP-43. TDP-43 harbors two RNA-recognition motifs, RRM1 and 2 (blue), and a C-terminal domain that has a G-rich N-terminal portion. The predicted prion domain spans this C-terminal domain.