Eunomica Blog: To be or not to be “a prion”: this is the question!

Il termine “prione” (acronimo di Proteinaceus Infective Only particle) venne coniato nel 1982 da Stanley Prusiner, quando lo usò per identificare l’agente infettivo responsabile della malattia di pecore e bovini, la scrapie. Prusiner aveva notato che l’agente infettivo in questione era di natura proteica, non conteneva acidi nucleici ed era resistente all’inattivazione con trattamenti che sono soliti degradare gli acidi nucleici stessi.

La caratteristica principale del prione è l’alta infettività e la capacità di propagarsi mantenendo una specifica conformazione tridimensionale, ovvero di replicarsi mantenendosi fedelmente uguale a sè stesso. Inoltre ai prioni è associato il salto di specie come quello pecora-bovino (Encefalopatia Spongiforme Bovina) o bovino-uomo (Morbo di Creutzfeldt-Jakob).

Dati recenti della letteratura scientifica stanno tentando di categorizzare le proteine responsabili di malattie neurodegenerative, quali la malattia di Alzheimer o il morbo di Parkinson, come proteine prioniche, ma riguardo questo si è aperto un acceso dibattito: proteine quali Aβ o tau hanno davvero tutte le caratteristiche dei prioni?

Tauopathies are a group of neurodegenerative diseases, they are characterized by the formation of tau aggregates, which are insoluble fibers that clog the cell up.

Alzheimer´s disease (AD) is one of the most devious forms of tauopathy that affects 30 million people worldwide and will affect more than 120 million by 2050.

Tau is a microtubule-associated protein that binds and stabilizes the network of microtubules within the cells. Once it is phosphorylated, tau becomes twisted and tangled and its ability to bind to microtubules is reduced, thus leading the entire neuron transport networks up to the collapse.

Prior studies show that in “test tube experiments” tau has the ability to propagate by adopting specific conformations, which show unique physical properties. In this recent paper, Marc Diamond and collaborators examined the ability of tau strains to self-propagate by maintaining their distinct conformation in living cells and organisms. The authors produced tau fibrils in vitro and used them to seed pathological inclusions containing fibrillar aggregates in the cells.

They isolated two cell clones that had a specific “phenotypical” morphology and characterized them in depth.

They noticed that once these clones were injected into naïve cells, they were able to stably propagate their own particular shape of inclusion from mother to daughter cells. Then, they injected transgenic mice with these strains and waited for the appearance of tauopathy. After three weeks, they collected the brains, which underwent both biochemical and histological analysis.

The authors found that these strains were stably inherited trough multiple generations, maintaining their unique pathological phenotypes.

The conclusion of this study brought Diamond and his collaborators to describe tau as a prion, since, according to them, the protein accounts for all the characteristics of prion strains.

But what do you think?

Isn´t this definition risked?

Prions are infectious agent, whereas there is no proof that amyloid proteins are.

The infectivity of neurodegenerative proteins must be demonstrated if we want the public audience to pick the idea of AD as a “prion” disease, otherwise this concept could be misleading.

Anyway, there is big news in this study!

By demonstrating that tau acts by propagating a specific strain conformation, Diamond and his collaborators try to relate the behavior of this protein to the human disease.

In fact, it stands to reason that different tauopathies come with their own “fingerprint” that, if we consider the result of this study, may be highly specific for patients.

Since many drugs fail at the clinical trial stage, we must consider the possibility that therapeutics is ineffective due to differences in tau´s conformers among patients.

This means that probably the AD pattern is much more complicated than we thought, and that there is still a long way to go to find effective new treatments for AD, but studying the behavior of amyloid proteins is the inevitable process to develop drugs that can turn out to be successful.

Bibliography

Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, Barker SJ, Foley AC, Thorpe JR2, Serpell LC, Miller TM, Grinberg LT, Seeley WW, Diamond MI (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82: 1271-1288.

Livia Civitelli, PhD