What’s In a Name? The Big Prion Debate

A review published last week in Science has once again sparked one of the great debates in neuroscience – namely, are all neurodegenerative diseases prions?

Prions have always been shrouded in controversy. Stanley Prusiner, who won the 1997 Nobel prize in Physiology and Medicine for his discovery of the infectious proteins, fought through years of belittling cynics. Once the prion phenomenon was accepted, Britain was struck by BSE (bovine spongiform encephalopathy or mad cow disease) and a national epidemic was feared.

Prions are unlike any other infectious diseases. Simply put, they are misfolded proteins that confer their misfolded state onto other, normal, cellular proteins. These misfolded proteins then clump together to form aggregates that disrupt cellular functions like protein transport and respiration. Finally, the cell dies. The protein that misfolds in all known prion disease has come to be known prion protein, or PrP for short.

The prion diseases (Kuru, BSE, FFI) aggressively attack neurons, and progressive quickly throughout the nervous system. Death usually occurs within a year.

Sugestion that common neurodegenerative diseases (e.g. Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobe Dementia (FTLD)) were the result of prions started as early as Stanley Prusiner in 1997. But in the past five years, these claims have gained more and more traction and today there is a certain level of acceptance in the neurodegenerative disease community that common neurodegenerative diseases are highly similar to prions.

But, the crucial question is whether neurodegenerative diseases are prions. Not prion like, not prionoid, but full-blown bona fide prions. This suggestion sends many in the community livid, they argue it could incite a national panic, that no good can come of accepting these diseases are prions.

Are all neurodegenerative diseases prions?

All common neurodegenerative diseases are associated with distinct proteins. What is surprising is that in all of these diseases their respective proteins misfold to form aggregates. If this sounds familiar to you, that’s because it’s incredibly similar to the way PrP causes neurodegeneration in prion diseases like Kuru.

But this in itself doesn’t implicate the proteins as the causative agents. For many years these proteins were thought to be the result of the disease, not its cause. It was thought that various genetic or environmental factors caused the disease, and then as a result of the disease these proteins began to misfold and aggregate.

A puzzling observation about the disposition of these proteins was made as early as 1991. Heiko Braak sectioned thousands of human brains and showed that tau is deposited in the entorhinal cortex and then follows a defined anatomical pathway throughout the brain as Alzheimer’s disease progresses. What this means is that tau aggregates in the entorhinal cortex at the early stages of the disease, and then spreads through the hippocampus to the rest of the cortex as the disease becomes more advanced.

Over the coming 20 years, it was shown that other proteins (such as alpha-synuclein) spread through the brain in this way. Many speculated about what caused this time delay in deposition. A number of theories were proposed (many of which are beyond the scope of this article) but the main idea was that some brain regions were just innately more susceptible than others to protein aggregation.

Then, in 2008, Li et al. found that misfolded alpha synuclein spread directly from cell to cell. Patients with Parkinson’s disease sometimes undergo a fetal graft whereby fetal neurons are implanted into their substantia nigra (which is affected before many other regions in the disease).

These fetal neurons are usually about 10 years old when the patients dies and therefore by many theories should be immune from signs of Parkinson’s disease. Amazingly, the study showed that alpha synuclein had moved into these immature neurons. The authors concluded the alpha synuclein must have been transferred between the cells. In other words, it spread like a prion.

Over the next 7 years, more and more evidence built up that alpha synuclein, and the other proteins involved in these diseases, are able to misfold and spread cell to cell in a prion-like manner. The only thing stopping many from calling them prions was their inability to be transmitted between organisms.

The final question

Can Alzheimer’s be caught? This is the golden question that has led many to argue that the disease is not a prion disease. No studies have found any evidence of infectivity in any of the common neurodegenerative diseases and it seems almost certain they are not infectious.

But that doesn’t mean they aren’t prions. If you are familiar with the full prion story, you will know their discovery is highly caught up in the Kuru outbreak in Papua New Guinea. Here, a number of tribes were involved in ritualistic cannibalism, whereby they would eat the brains of the dead. It is here that many believe the deadly Kuru prion spread and after cannibalism was stopped the disease was almost entirely wiped out.

Ritualistic cannibalism is an extraordinarily unusual activity and it seems to many that only in unusual circumstances are prions infectious: the BSE outbreak, for instance, where millions of pounds of meat were infected with prions for years. Variant CJD (another prion disease) has been known to be infectious via the injection of human growth hormone collected from individuals that died of CJD.

It is unlikely this debate will be resolved anytime soon. Many would argue Prusiner stands to gain mightily if we do end up classifying Alzheimer’s and other neurodegenerative diseases as prion diseases. As such, he will push for the name long after his retirement – whether that means they truly are prions is a different story.


Braak H, & Braak E (1991). Neuropathological stageing of Alzheimer-related changes. Acta neuropathologica, 82 (4), 239-59 PMID: 1759558

Goedert, M. (2015). Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled A , tau, and  -synuclein Science, 349 (6248), 1255555-1255555 DOI: 10.1126/science.1255555

Kim BH, Lee HG, Choi JK, Kim JI, Choi EK, Carp RI, & Kim YS (2004). The cellular prion protein (PrPC) prevents apoptotic neuronal cell death and mitochondrial dysfunction induced by serum deprivation. Brain research. Molecular brain research, 124 (1), 40-50 PMID: 15093684

Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Björklund A, Widner H, Revesz T, Lindvall O, & Brundin P (2008). Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nature medicine, 14 (5), 501-3 PMID: 18391963

Zhang J, & Dong XP (2012). Dysfunction of microtubule-associated proteins of MAP2/tau family in Prion disease. Prion, 6 (4), 334-8 PMID: 22874672

Image via Photoprofi30 / Shutterstock.

John Cousins, BSc, MBChB

John Cousins is a graduate of Neuroscience from University College London (UCL). He is currently a post graduate medical student (MbCHb) at The University of Warwick and is particularly interested in pain and neurodegenerative diseases. He is the founder of SimpleNeuroscience.com.
See All Posts By The Author