Just a quick comment as i have to get to lab meeting, but i think the paper you refer to is very interesting! We know that transplanted healthy grafts are susceptible to host-to-graft spread of Lewy body pathology (Kordower 2008, and others). This new study suggests that perhaps that process is not as robust as one might have imagined, and there may be host-specific factors that influence the susceptibilty of the grafts to the host pathology. Conflicting data like this is awesome, it makes us dig deeper, think more, come up with new hypotheses, and ultimately advance our understanding of what's really going on.

It doesn't really refute anything as graft studies are not the only ones that show spreading. It does, however, remind us to do proper controls and not to jump into conclusions.

Thank you so much for your contribution. But, is it possible that mouse models are not a trustworthy animal model in this case. And is there any study on these models to compare different animal models to see which one is mostly comparable with what is happen in patients?

Mouse models are not perfect but they reproduce familiar PD pretty well. Also, various papers have found some spreading in human brain. Maybe grafts are somewhat resistant to it, it's smth that would be interesting to look into.

Thank you Dr. Breydo for you explanation.

Maybe this article is not an exact study to refute the prion-like hypothesis because cell-to-cell transmission of pathology to aged and damaged neurons in a patient can not compare with young fetal transplanted cells with healthy and strong proteolytic systems. Also, for future stem cell based therapy scientists should have this point in their mind if they want the transplanted cells to remain healthy in patients brain tissue for years. Is this thought correct? Any other opinion here?

I think you are right Amir. As we discussed in our journal club which you hand it in last week, aging is a key factor in neurodegenerative diseases including Parkinson' disease. Due to oldness, the capability of cells for some process including autophagy and related proteolytic systems would be decreased. In the above article, the authors have been used human fetal midbrain cells for transplantation. As you know, while we are trying to use primary cell culture, the best choice for us is the young animals or even embryo cells due to some reasons. One reason is that in young animals the cells are also young and have a strong activity and the factors for cell survival are vigorous. In such case, the autophagy and related proteolytic systems have their perfect activity and can remove or degrade the out of order or aggregated proteins. So, we face with the fact that after 14 years the human fetal midbrain cell which grafted to the patients have not infected by aggregation forms of protein through prion-like hypothesis or cell-to-cell transmission (Brundin et al,. Luk et al,. 2012, in JEM and Science, Masuda-Suzukake et al. 2013 in Brain) which is pathology of Parkinson' disease may be due to their high activity to remove or degrade the aggregated form of protein which entered them.

Lawrence I would love for the prion hypothesis to be wrong but those few studies you mention are countered by a seemingly countless number of studies that overwhelmingly support the prion hypothesis. I absolutely have so much respect for Laura manuelidis and her pursuit of a virus/bacteria, but I am no longer so sure she will find one! Science eventually has a way of showing us that science fiction isn't too far-fetched after all.

In the field of Parkinson's disease, prion-like expansion theory expressing that misfolded, prefibrillar or fibrillar forms of a protein called alpha-synuclein can transfer from cell to cell and can induce the fibrillation of endogenous alpha-synuclein proteins through a seeding procedure in the new cells, which leads to pathology propagation in brain tissue. Although, the mechanism is somehow similar to prion disease but it is just prion-"like" theory after the concept of prion expansion. In fact, I think, it is not important that prion hypothesis are rejected now or not because this theory is completely different and just use the name of a famous neural disease as a model to convey a concept in the Parkinson's disease. Please tell me if it is not true.

TSE was the first disease for which prion hypothesis has been proposed. If it turned out that prion hypothesis is invalid for TSE, it wouldn't make it automatically invalid for other diseases but it would raise a lot of questions. And quoting Salon articles from 1997...

In the world of science there are lots of hypotheses and papers which are agreement and support each other and of course, we face with some of them that are refute or rejected each other. One example is: Nanobacter. There is a famous expression said: Nanobacter; fact or fiction? Or something like: Nanobacter; to be or not to be? Nevertheless, it is proved that Nanobacter has role in some diseases including heart and kidney ailments. However there are some controversy reports concerning their origin. Are they alive organisms or their just a calcified particles or something else?

Any way I come back to our discussion. Although, there are some reports regarding the rejection of prion hypothesis as Lawrence has mentioned. However there are lots of reports confirm them. First we have to prospect them carefully to get more details regarding their features and natures. Second, we have to see how many paper and clue authorized them and how many refute them and not to jump to conclusion by a few articles as Daryl has noted. Anyhow about the prion-like hypothesis concerning the Parkinson’ disease I agree with Amir and Leonid due to transmission the alpha-synuclein from cell to cell which has been shown in some papers in vitro and in vivo experiments. In fact, alpha-synuclein is spread form cell to cell just like a prion and generate the pathology of Parkinson’ diseases.

Marketing efforts by Prusiner aside, the real issue is whether prions prepared from recombinant proteins can be disease agents. And there have been several recent studies showing that it is indeed the case (1,2). One of them, btw, co-authored by Bob Rohwer whose earlier work you’re citing. As for lack of detectable prions in some cases, it has been since shown that the original method of prion detection used by Prusiner misses quite a few of them (3). Regarding anti-amyloid drugs, a number of them are effective in mice and several are in human clinical trials (4).

References:

1. Wang, F., Wang, X., Yuan, C. G., and Ma, J. (2010) Generating a prion with bacterially expressed recombinant prion protein. Science 327, 1132-1135

2. Makarava, N., Kovacs, G. G., Bocharova, O., Savtchenko, R., Alexeeva, I., Budka, H., Rohwer, R. G., and Baskakov, I. V. (2010) Recombinant prion protein induces a new transmissible prion disease in wild-type animals. Acta Neuropathol 119, 177-187

3. Colby, D. W., Wain, R., Baskakov, I. V., Legname, G., Palmer, C. G., Nguyen, H. O., Lemus, A., Cohen, F. E., DeArmond, S. J., and Prusiner, S. B. (2010) Protease-sensitive synthetic prions. PLoS Pathog 6, e1000736

4. Serrano-Pozo, A., William, C. M., Ferrer, I., Uro-Coste, E., Delisle, M. B., Maurage, C. A., Hock, C., Nitsch, R. M., Masliah, E., Growdon, J. H., Frosch, M. P., and Hyman, B. T. (2010) Beneficial effect of human anti-amyloid-beta active immunization on neurite morphology and tau pathology. Brain 133, 1312-1327

Of course in 1984 it was not well understood. But that was 30 years ago. I agree that when Prusiner got a Nobel prize he hasn't proven conclusively that prions are real. But the real issue here are not Prusiner's PR and marketing efforts. It's whether a misfolded/aggregated protein in the absence of DNA or RNA can transmit information. And it has been shown pretty conclusively that it can. In some cases this will lead to disease, in others (e.g. CPEB or yeast prions) it has a beneficial role.

How about this recent paper of Manuelidis that trashes prion fiction at last?

J Cell Biochem. 2016 Jan 16. doi: 10.1002/jcb.25495. [Epub ahead of print]

CJD and Scrapie Require Agent-Associated Nucleic Acids for Infection.

Botsios S1, Manuelidis L1.

Author information

Abstract

Unlike Alzheimer's and other neurodegenerative diseases, Transmissible Spongiform Encephalopathies (TSEs) are all caused by actively replicating infectious particles of viral size and density. Different strain-specific TSE agents cause CJD, kuru, scrapie, and BSE, and all behave as latent viruses that evade adaptive immune responses and can persist for years in lymphoreticular tissues. A foreign viral structure with a nucleic acid genome best explains these TSE strains and their endemic and epidemic spread in susceptible species. Nevertheless, it is widely believed that host prion protein (PrP), without any genetic material, encodes all these strains. We developed rapid infectivity assays that allowed us to reproducibly isolate infectious particles where >85% of the starting titer separated from the majority of host components, including PrP. Remarkably, digestion of all forms of PrP did not reduce brain particle titers. To ask if TSE agents, as other viruses, require nucleic acids, we exposed high titer FU-CJD and 22L scrapie particles to potent nucleases. Both agent-strains were propagated in GT1 neuronal cells to avoid interference by complex degenerative brain changes that can impede nuclease digestions. After exposure to nucleases that are active in sarkosyl, infectivity of both agents was reproducibly reduced by >99%. No gold-stained host proteins or any form of PrP were visibly altered by these nucleases. In contrast, co-purifying protected mitochondrial DNA and circular SPHINX DNAs were destroyed. These findings demonstrate that TSE agents require protected genetic material to infect their hosts, and should open reinvestigation of essential agent nucleic acids. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.