Prions Reveal How Alzheimer’s and Parkinson’s Disease May Spread

Are neurodegenerative diseases like Alzheimer’s and Parkinson’s contagious? Are they similar to prion diseases such as mad cow disease? If you’ve been following recent headlines, this might seem like a possibility, but is it accurate?

Professor Joel Watts, an alumnus of U of T’s Department of Laboratory Medicine and Pathobiology, is a prion disease expert. Watts, also a professor of the U of T’s Department of Biochemistry, explains how prions could help shed light on how other neurodegenerative diseases work. He provides a glimpse into the future of this growing area of research.

What are prion proteins and how can they cause disease?
Originally, prions were defined as “proteinaceous infectious particles” that cause degenerative brain diseases such as Creutzfeldt-Jakob disease (CJD) in humans, mad cow disease, and scrapie in sheep. The term prion was coined to distinguish these diseases from those caused by viruses or bacteria. The hallmark of prions is that there are two versions of the same protein: the normal version is properly folded and is benign; the other version is misfolded, forms plaques and causes disease. The misfolded version can recognize the normal version and convert it into the disease-associated form. This is why prions are infectious and can spread throughout the brain.

What are the similarities between prion diseases and other neurodegenerative diseases like Alzheimer’s?
Until recently, it was thought that there was only one protein that could become a prion: the prion protein, which is the protein associated with CJD, scrapie, and related disorders.  It is becoming increasingly clear that other protein clusters, such as those that cause Alzheimer’s disease, Parkinson’s disease, multiple system atrophy and amyotrophic lateral sclerosis (ALS) could replicate. This is why some researchers have started to refer to these protein clusters as prions, even if there is no evidence that the associated diseases are infectious.

What are the differences?
While there are some similarities between CJD and Alzheimer’s, there are also many differences. For instance, CJD is a rapidly progressive dementia while Alzheimer’s progresses more slowly. Also, Alzheimer’s is very common — up to 40 per cent of the population may be at risk for developing the disease if they live long enough. CJD is rare and only affects approximately one person per million. Although both diseases feature abnormal protein clusters in the brain, these clumps are composed of completely distinct proteins.

Could Alzheimer’s or Parkinson’s be contagious?
There is absolutely no evidence that Alzheimer’s or Parkinson’s disease is contagious or can be transmitted naturally from person-to-person. There’s also no evidence that these diseases have been accidentally transmitted from person-to-person via a medical procedure (as has occurred with the prion diseases). However, from a theoretical standpoint, there is certainly enough evidence to suggest that at least some parts of these diseases could be transmissible. When researchers inject Alzheimer’s and Parkinson’s clusters into the brains of mice, these mice develop similar plaques to those found in patients. But since people don’t typically go around sticking other people in the brain with needles, this potential route of transmission would likely not apply to human disease.

Why do we know so little about prion diseases and why they progress?
The idea that prion diseases are caused by an infectious protein, and not some sort of mysterious virus, has only gained widespread acceptance within the last 20 years or so. That’s why the study of prions and prion diseases is still in its infancy. Despite the headline-grabbing nature of these diseases, they remain exceedingly rare and are therefore not necessarily an urgent priority for funding agencies or an attractive target for big pharmaceutical companies. Thankfully, Canada has become a world leader in prion disease research, in part due to cases of mad cow disease in Alberta.

What is your lab studying in regard to Alzheimer’s disease and its relation to prion diseases?
My lab is studying Abeta, which is a protein fragment closely associated with Alzheimer’s. We’re trying to understand how and why Abeta plaques spread in a prion-like fashion throughout the brain and whether this phenomenon underlies disease progression in Alzheimer’s patients. In particular, we’re studying whether different types of Abeta plaques cause Alzheimer’s. In prion disease, there are different types of prions that create clusters in a variety of shapes. We’re interested in seeing whether different types of Abeta plaques cause Alzheimer’s to manifest in different ways.

What do you find most interesting about prion disease, and where do you think research in this area is headed?
I enjoy working on something that goes against so many established biological dogmas. At one point, the concept of an infectious agent that could replicate in the absence of DNA or RNA was considered impossible, and the existence of two distinct stable folds of a single protein was a direct violation of a biochemical principle. As a result, despite their rarity, I think that prions and prion diseases are inherently interesting and can tell us a lot about fundamental biochemical mechanisms that may have more widespread implications in biology. The idea that Alzheimer’s, Parkinson’s and ALS may also involve prion-like phenomena has exploded in recent years and is almost certainly the hottest topic in the field. This has brought many new ideas and investigators to the prion field, and I’m hopeful that this synergy will lead to many new insights that will ultimately result in the development of effective treatments for these devastating disorders.