Neurodegenerative diseases: expanding the prion concept

Abstract

The prion paradigm has emerged as a unifying molecular principle for the pathogenesis of many age-related neurodegenerative diseases. This paradigm holds that a fundamental cause of specific disorders is the misfolding and seeded aggregation of certain proteins. The concept arose from the discovery that devastating brain diseases called spongiform encephalopathies are transmissible to new hosts by agents consisting solely of a misfolded protein, now known as the prion protein. Accordingly, "prion" was defined as a "proteinaceous infectious particle." As the concept has expanded to include other diseases, many of which are not infectious by any conventional definition, the designation of prions as infectious agents has become problematic. We propose to define prions as "proteinaceous nucleating particles" to highlight the molecular action of the agents, lessen unwarranted apprehension about the transmissibility of noninfectious proteopathies, and promote the wider acceptance of this revolutionary paradigm by the biomedical community.

Keywords: Alzheimer's disease; Parkinson's disease; amyloid; cell-to-cell spreading; disease progression; prion; proteopathy; synuclein; tau; transmission.

Figure 1

The prion paradigm of seeded protein aggregation. A schematic diagram shows the hypothetical series of events leading from the misfolding and self-aggregation of protein molecules to the formation of characteristic lesions. The assemblies that act as seeds for the templated misfolding of other molecules can vary in size from small oligomers to large polymers. These seeds initiate and sustain the disease process and may be the agents by which the aggregates proliferate and spread within the nervous system. In addition, small, oligomeric assemblies have been identified as cytotoxic agents in several instances. The lesions that result from the seeding cascade can occur as intracellular inclusions (such as neurofibrillary tangles or Lewy bodies) or extracellular masses (such as amyloid plaques).

Figure 2

Prion protein immunoreactivity (purple) and spongiform degeneration in the neocortex of a patient who had died of Creutzfeldt-Jakob disease. Nissl counterstain.

Figure 3

Senile [amyloid-β (Aβ)] plaque and neurofibrillary (tau) tangles in Alzheimer’s disease. (a) Light micrograph of hippocampal tissue that has been dual-immunostained for Aβ (brown in an Aβ plaque) and hyperphosphorylated tau (purple in neurofibrillary tangles). (b) Electron micrograph of a mass of extracellular amyloid fibrils in an Aβ plaque. (c) Electron micrograph of intraneuronal fibrillar polymers of tau protein, the ultrastructural components of neurofibrillary tangles. Labels denote two paired helical filaments.

Figure 4

α-Synuclein-immunoreactive lesions (brown) in the neocortex of a patient with Lewy body disease. The labels indicate Lewy bodies and a Lewy neurite. Nissl counterstain.