Inducible proteopathies

Abstract

Numerous degenerative diseases are characterized by the aberrant polymerization and accumulation of specific proteins. These proteopathies include neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and the prion diseases, in addition to diverse systemic disorders, particularly the amyloidoses. The prion diseases have been shown to be transmissible by an alternative conformation of the normal cellular prion protein. Other proteopathies have been thought to be non-transmissible, but there is growing evidence that some systemic and cerebral amyloidoses can be induced by exposure of susceptible hosts to cognate molecular templates. As we review here, the mechanistic similarities among these diseases provide unprecedented opportunities for elucidating the induction of protein misfolding and assembly in vivo, and for developing an integrated therapeutic approach to degenerative proteopathies.

Figure 1.

Spongiform degeneration (arrow) and the accumulation of prion protein (arrowhead) are consistent pathological features of prion disease, along with astrocytosis and neuronal degeneration. Shown is a section of neocortex from a patient who died of idiopathic Creutzfeldt-Jakob disease, labeled using the anti-PrP antibody 3F4 (Nissl counterstain). Bar = 50μm.

Figure 2.

A hypothetical pathway leading from normally folded, monomeric protein to multimeric assemblies such as small oligomers, protofibrils and amyloid fibrils. In this instance, a particular monomeric protein (circle) assumes an atypical β-sheet-rich fold (hexagon), either as a stochastic or seeded event. This corrupted protein then impels the templated misconformation and consequent self-assembly of endogenously produced, cognate proteins. Multimeric protein aggregates can exist in multiple 3D forms consisting of various numbers of monomers; it is likely that multimers can themselves feed back into the proteopathic cascade as seeds. ‘Strain’ differences in inducibility appear to be coded in subtle conformational variations in proteins. There might be several pathways leading to different higher order assemblies. The biological activity of specific multimers, and the conditions that favor each step in the pathogenic sequence in vivo, remain incompletely understood.

Figure 3.

The interaction between the agent and host in the induction of disease by a proteopathic agent. By definition, a benign protein (blue square) is incapable of transmitting disease. An inductive agent (red hexagon) is pathogenic only in the context of a permissive environment (top). Such environments might include: A configuration of the cognate protein that is conducive to templating (red circles); increased production or sequestration of the cognate protein by the host; and/or the presence of essential cofactor(s) (green stars). A restrictive host environment, by contrast, might consist of a protein configuration that is resistant to templating (blue circles, bottom), sub-optimal protein levels, and/or the absence of cofactors. The role of soluble oligomeric species in seeding-induced aggregation and cytopathology remains to be defined.