Department of Medical Education, Geisinger Commonwealth School of Medicine, 525 Pine Street, Scranton, PA, 18509, USA.
Theory Biosci. 2023 Jun;142(2):143-150. doi: 10.1007/s12064-023-00389-x. Epub 2023 Apr 5.
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.
常染色体显性疾病通常具有与年龄相关的发病。在这里，我主要关注由 PRNP 基因突变引起的遗传性朊病毒病（gPrD）。虽然 gPrD 通常发生在中年或之后，但具体的发病年龄存在很大的可变性。这种可变性可能发生在具有相同 PRNP 突变的患者中；在某些情况下，这些差异不仅存在于家族之间，甚至存在于同一家庭内部。尚不清楚为什么当致病突变从出生时就存在时，gPrD 的发病通常会延迟数十年。遗传性朊病毒病的小鼠模型会表现出疾病；然而，与人类 gPrD 通常需要数十年才能表现出疾病不同，小鼠模型在数月内就会出现疾病。因此，朊病毒病的发病时间与物种寿命成正比；然而，尚不清楚为什么会这样。我假设 gPrD 的起始强烈受到衰老过程的影响；因此，疾病的发病与比例功能年龄（例如，小鼠与人类）有关。我提出了一些方法来检验这一假设，并讨论了其对通过抑制衰老来延缓朊病毒病的意义。
