While mice succumb to prion disease in their brief lifespans, humans can take decades to manifest symptoms—what underlies this distinction and what insights does it offer for prion disease and potential reatments?

Functional age and onset of autosomal dominant genetic prion disease

While mice succumb to prion disease in their brief lifespans, humans can take decades to manifest symptoms—what underlies this distinction and what insights does it offer for prion disease and potential treatments?

Mice develop prion disease within their short lifespans, yet the process can take decades for humans. Why does this difference exist, and what can it tell us about prion disease and possible therapy?

Prion disorders are caused by an altered form of the prion protein; this abnormally folded protein causes similar folding in other prions, resulting in a rapid increase of these pathological brain proteins and the symptoms of prion disease.  There are four basic kinds of human prion-related diseases: sporadic, genetic (inherited), iatrogenic (acquired; e.g., from a medical procedure), and variant (“mad cow disease”).

This work focuses on genetic prion disease (gPrD), a fatal, autosomal dominant (inheritance from one parent is sufficient) neurological disorder. GPrD patients have prion gene mutations, making prion conversion into the disease-causing form more likely. Autosomal dominant diseases typically have an age-related onset, with increased risk as one ages. Thus, gPrD, similar to sporadic prion disease, usually manifests in middle age (or older). Importantly, it is unknown why gPrD onset is typically delayed for decades when the disease-causing mutation is present from birth. Is ageing related to disease development?

Mouse models of gPrD exist and manifest at least some signs of disease within the short lifespan of laboratory mice.  The onset of symptoms typically occurs at what would be “middle” or “old” age for mice (six months to two years). This contrasts with human gPrD, which typically requires decades to manifest.  Therefore, the time of development of prion disease differs between mice and humans in an absolute sense, i.e., in the total time required for onset. Therefore, gPrD onset in humans and mice is proportional to each lifespan; in both organisms, it is when “middle age” occurs, even if the absolute time required is markedly different (months to two years for mice; decades for humans).

Credit. Midjourney

Alternate hypotheses

Before we consider the main hypothesis, it is important to note two alternative explanations for why the onset of gPrD is longer in humans. First, prion conversion may differ between mice and humans, being more rapid in mice.  The reasons must be determined if this is the case, as they may lead to therapies that delay human conversion.  If we assume that mouse vs. human prion conversion is similar, why is the progression to disease so much more rapid in mice?

A second explanation is that the brains of mice are much smaller than those of humans, so less time is required to damage enough of the brain to cause disease.  A counterargument is that the larger human brain, containing more cells and prion proteins, should exhibit a greater probability of prion conversion. If humans have more cells and more prions than mice, then there is a greater chance that abnormal prions will form. This would compensate for brain size differences, making the risk even greater.

What else can explain the greater time required for prion disease in humans?

Main hypothesis

What if prion disease is influenced by ageing itself?  We hypothesize that disease onset is related to functional age.  What we mean by functional age is how ageing is physically manifested, which is not the same as chronological age. Two individuals may be the same chronological age, but one may exhibit increased signs of ageing compared to the other.  Envision two people of the same calendar age, one having more “wear and tear” on their body and a greater functional age. The factors that affect this “wear and tear” could make prion conversion more rapid.

Testing the main hypothesis and implications

The hypothesis (Fig. 1) is that the onset of prion disease is influenced by functional age, with greater risk with increased functional age. Understanding how this occurs could lead to anti-gPrD therapies focusing on the repression of functional ageing. 

Figure 1. Visual outline of the main hypothesis
     Credit. Author

How could we test this hypothesis? One approach would be to use animal models of prion disease.  GPrD model mice can be mated with mice containing mutations that accelerate or inhibit the ageing process, and we could observe how rapidly the offspring manifest symptoms of prion disease. One would expect mice with accelerated ageing to develop signs of prion disease more rapidly and mice with inhibited ageing to exhibit delayed symptoms. 

One could also look at human patients to see if there is any correlation between the age of onset of prion disease and signs of functional ageing, such as telomere length (the tips of chromosomes are shortened with age and various factors accelerate this), chronic inflammation, and other age-related processes.

If this hypothesis is correct, interventions that retard ageing will decrease the probability of prion conversion.  If disease onset can be delayed long enough, the affected individual may die of other causes before onset, or at least the period of disease-free life can be extended.  Treatments based on inhibiting ageing can complement other potential therapies against prion disease, such as decreasing prion protein levels.

Even if the hypothesis turns out to be false, studying it will still be helpful since discovering why human prion disease takes so long could lead to new therapies. In addition, findings generated from investigating gPrD might also apply to the sporadic forms of prion disease, which affect more people than gPrD.


Journal reference

Bordonaro, M. (2023). Hypothesis: functional age and onset of autosomal dominant genetic prion disease. Theory in Biosciences142(2), 143-150. https://doi.org/10.1080/02667363.2022.2155932

Michael Bordonaro, PhD, is an associate professor of molecular biology at the Geisinger Commonwealth School of Medicine. Dr. Bordonaro obtained his PhD in the biological sciences from Fordham University in Bronx, New York. Additionally, he completed a postdoctoral fellowship in the Department of Oncology at the Montefiore Medical Center, Bronx, New York. Dr. Bordonaro subsequently held the position of associate research scientist at the Yale University School of Medicine and has also served as a research coordinator for Keren Pharmaceutical. In 2008, Dr. Bordonaro joined the faculty of The Geisinger Commonwealth School of Medicine.