Biology and genetics of prions causing neurodegeneration

Abstract

Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests.

Figure 1

Neurodegeneration caused by prions. (Sporadic NDs) In sporadic neurodegenerative diseases (NDs), wild-type (wt) prions multiply through self-propagating cycles of posttranslational modification during which the precursor protein (green circle) is converted into the prion form (red square), which generally is high in β-sheet content. Pathogenic prions are most toxic as oligomers and less toxic after polymerization into amyloid fibrils. The small polygons (pale yellow) represent proteolytic cleavage products of the prion. Depending on the protein, the fibrils coalesce into Aβ amyloid plaques in Alzheimer’s disease (AD), neurofibrillary tangles in AD and Pick’s disease, or Lewy bodies in Parkinson’s disease and Lewy body dementia. Drug targets for the development of therapeutics (beige octagons): (1) lowering the precursor protein, (2) inhibiting prion formation, and (3) enhancing prion clearance. (Inherited NDs) Late-onset heritable neurodegeneration argues for two discrete events: the first event (green rectangle I) is the synthesis of mutant precursor protein (green circle) and the second event (yellow rectangle II) is the age-dependent formation of mutant prions (red square). The yellow bar with diagonal lines in the DNA structure represents mutation of a base pair within an exon, and the small yellow circles with diagonal lines signify the corresponding mutant amino acid substitution.