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Review
. 2016 Feb 3;89(3):433-48.
doi: 10.1016/j.neuron.2016.01.026.

Prions and Protein Assemblies that Convey Biological Information in Health and Disease

David W Sanders  1 , Sarah K Kaufman  1 , Brandon B Holmes  1 , Marc I Diamond  2
Affiliations
Review

Prions and Protein Assemblies that Convey Biological Information in Health and Disease

David W Sanders et al. Neuron. .

Abstract

Prions derived from the prion protein (PrP) were first characterized as infectious agents that transmit pathology between individuals. However, the majority of cases of neurodegeneration caused by PrP prions occur sporadically. Proteins that self-assemble as cross-beta sheet amyloids are a defining pathological feature of infectious prion disorders and all major age-associated neurodegenerative diseases. In fact, multiple non-infectious proteins exhibit properties of template-driven self-assembly that are strikingly similar to PrP. Evidence suggests that like PrP, many proteins form aggregates that propagate between cells and convert cognate monomer into ordered assemblies. We now recognize that numerous proteins assemble into macromolecular complexes as part of normal physiology, some of which are self-amplifying. This review highlights similarities among infectious and non-infectious neurodegenerative diseases associated with prions, emphasizing the normal and pathogenic roles of higher-order protein assemblies. We propose that studies of the structural and cellular biology of pathological versus physiological aggregates will be mutually informative.

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Figures

Figure 1
Figure 1. Steps in trans-cellular propagation
Trans-cellular propagation of prions is likely to involve escape from a first-order cell, binding to a second-order cell, uptake into a second-order cell, seeding of native monomer, and fragmentation and amplification of the seeded aggregates. (A) Escape of prions from a first-order cell could occur by direct release into the extracellular space. This may be driven by unconventional secretion, cell death, or membrane penetration. (B) Alternatively, prions could escape in exosomes, or (C) could directly move to neighboring cells via tunneling nanotubes. (D) In the exosomal pathway, cell entry would presumably occur via vesicle fusion. (E) More likely, prions bind to heparan sulfate proteoglycans (HSPGs) to trigger macropinocytosis. (F) It is theoretically possible that prions gain entry by another form of receptor-mediated endocytosis, although there is not clear evidence for this. (G) Prions escape the lumen of vesicles to encounter cognate monomer. (H) The seed acts as a template for recruitment of monomer to amplify the prion structure. This likely involves a replication machinery that may also be involved in fibril fragmentation to amplify the number of seeds, which then repeat the cycle of propagation to other cells.
Figure 2
Figure 2. Prion replication mechanisms and network involvement link strains to biological phenotype
The various steps in replication of a prion provide an explanation for how strains might exhibit different rates of progression, types of neuropathology, and involvement of specific networks. (A) Biophysical and biochemical parameters govern strain replication efficiency. A single protein monomer can adopt multiple potential amyloid configurations, illustrated by squares vs. triangles. Strain-specific fibril stability and the interaction with chaperone/replication machinery may determine the fragmentation rate and production of seeds. This likely determines the rate of spread and disease progression, with strong strains featuring more rapid phenotypes. (B) A strain must propagate pathology by entering a neuron and initiating seeding and subsequent replication of a particular structure. The newly formed aggregates will accumulate in certain regions of the cell, possibly through interaction with specific factors, and may be differentially transported in axons. Finally, strains may have differential rates of release and/or toxicity at the cell membrane/synapse that govern transfer to other cells. Each of these steps may be influenced by strain conformation. (C) Unique strains may target different cell types and neural networks to cause syndromic variation. Aggregate conformers (square vs. triangle) may target one cell type more readily than another. This could be based on parameters discussed above: cell entry, replication, and trans-cellular propagation rates. Distinct neuronal networks might thus be vulnerable to particular strains.
Figure 3
Figure 3. Formation of higher-order assemblies in signaling, RNA metabolism, and disease
(A) Diverse proteins form micron-sized signalosomes to drive cellular responses. These structurally heterogeneous complexes rapidly assemble via polymerization domains in core proteins, and amplify an upstream signal. They form particles that recruit multiple accessory factors through adaptor domains. The resulting signalosome triggers all-or-none signaling responses such as cell death. The amplification and trans-cellular spread of signals may involve machinery similar to that used by prions. (B) Proteins with low-complexity sequences (LCS) undergo liquid-liquid phase separation to form large, dynamic membraneless organelles as part of RNA metabolism. Cell signals regulate their assembly and disassembly, which is based on self-association of the LCS to create a high concentration of the functional domain. In ALS and potentially other diseases, these liquid complexes may undergo an aberrant transition to a solid (i.e. fibrillar) form that becomes a self-propagating prion. Similar to other prions (e.g. PrP, tau), a cellular amyloid replication machinery may fragment these structures to produce additional seeds that spread between cells to drive progressive pathology.
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