Hypothesis: functional age and onset of autosomal dominant genetic prion disease.

Abstract

Autosomal dominant diseases typically have an age-related onset. Here, I focus on genetic prion disease (gPrD), caused by various mutations in the PRNP gene. While gPrD typically occurs at or after middle age, there can be considerable variability in the specific age of onset. This variability can occur among patients with the same PRNP mutation; in some cases, these differences occur not only between families but even within the same family. It is not known why gPrD onset is typically delayed for decades when the causative mutation is present from birth. Mouse models of gPrD manifest disease; however, unlike human gPrD, which typically takes decades to manifest, mouse models exhibit disease within months. Therefore, the time to onset of prion disease is proportional to species lifespan; however, it is not known why this is the case. I hypothesize that the initiation of gPrD is strongly influenced by the process of aging; therefore, disease onset is related to proportional functional age (e.g., mice vs. humans). I propose approaches to test this hypothesis and discuss its significance with respect to delaying prion disease through suppression of aging.