Evidence for prion-like mechanisms in several neurodegenerative diseases: potential implications for immunotherapy

Abstract

Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases. While the impact of TSEs on human health is relatively minor, these diseases are having a major influence on how we view, and potentially treat, other more common neurodegenerative disorders. Until recently, TSEs encapsulated a distinct category of neurodegenerative disorder, exclusive in their defining characteristic of infectivity. It now appears that similar mechanisms of self-propagation may underlie other proteinopathies such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. This link is of scientific interest and potential therapeutic importance as this route of self-propagation offers conceptual support and guidance for vaccine development efforts. Specifically, the existence of a pathological, self-promoting isoform offers a rational vaccine target. Here, we review the evidence of prion-like mechanisms within a number of common neurodegenerative disorders and speculate on potential implications and opportunities for vaccine development.

Figure 1

Proposed models of PrP^Sc-induced misfolding of PrP^C. The prion protein normally adopts a mainly alpha-helical structure under homeostatic cellular conditions (PrP^C). PrP^C can potentially misfold to predominantly beta-sheet structure, thereby adopting an infectious and disease-causing conformation (PrP^Sc). Many possible intermediate conformations of variable secondary structure, composition can be adopted during transition from PrP^C to PrP^Sc (PrP^Int, denoted as a single structure for clarity).

Figure 2

Potential effector functions of immunotherapeutic antibodies in proteinopathies. Misfolded protein-specific antibody responses could function in a neutralizing fashion to bind and block extracellular misfolded protein from spreading to adjacent cells and tissues. These antibodies could also act upon misfolded proteins still associated with diseased cells, thereby decreasing local cell-cell spread, disallowing release of further misfolded protein, and marking cells for destruction by antibody dependent cell mediated cytotoxicity or complement activation.