Does a prion hypothesis explain Parkinson's? The jury is still out

[Farooqji]

In recent years, neuroscientists have debated whether prion-like activity damages the brain in people with Parkinson's, but scientists in Japan, after an exhaustive analysis, report no evidence of misfolded, transmissable proteins persisting at the core of the disease

m.medicalxpress.com/news/20...

[park_bear]

By the "no evidence" comment the investigators were merely citing the current state of knowledge, rather than saying they looked and did not find such evidence. Yet another abysmal example of what passes for science reporting. Actual study:

pnas.org/content/early/2019...

"Lewy bodies (LBs), which mainly consist of α-syn, are neuropathological hallmarks of patients with Parkinson’s disease (PD). Recently, it has been reported that aggregates of α-syn with cross-β structures are capable of propagating within the brain in a prionlike manner. However, there is still no evidence that such propagation occurs in the patient’s brain. [emphasis added]

Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and confirmed that aggregates of α-syn with a cross-β structure exist in brains of PD patients. Our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation and propagation of amyloid fibrils of α-syn."

[sharoncrayn in reply to park_bear]

Parkie_Bear:

Once again you are wrong.as usual. You quote the critical sentence stating they did "look".

" Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and confirmed that aggregates of α-syn with a cross-β structure exist in brains of PD patients."

I think it is very clear that they "looked". They "examined". No less from the autopsy of brains of PD patients. What more do you want? What don't you understand?

Then...they "confirmed". Pretty clear to me.

Have a good holiday.

Sharon

[park_bear in reply to sharoncrayn]

They looked for and found "structures". Propagation is a dynamic process. They did nothing to address this issue, nor did they claim to have done so.

[sharoncrayn in reply to park_bear]

Propagation was not the central issue of this study.

They "report no evidence of misfolded, transmissable proteins persisting at the core of the disease."

"They found no signs of prion-like activity following microbeam X-ray diffraction analyses of autopsied human brain tissue from patients with Parkinson's. The finding suggests no support for a prion hypothesis in Parkinson's disease."

"This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-β structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn."

As to the Prion theory re: PD, The German study (2016) from the German Center for Neurodegenerative Diseases refutes the prion theory for PD conclusively as does this study.

Obviously, the title of this thread was grossly in error. Nothing unusual from this individual.

Worth re-reading the study

[Farooqji in reply to sharoncrayn]

Thanks for taking time and correcting us

[sharoncrayn in reply to Farooqji]

My pleasure. I do admire that you have come up with some interesting scientific studies.

[park_bear in reply to sharoncrayn]

The first and second passages that you quoted do not appear in the study, they appear in erroneous news report. The third passage you quoted does appear in the study but it does not support your contention. So you have proven nothing.

[sharoncrayn in reply to park_bear]

I quoted the MedicalExpress article. You think it is erroneous? Prove it. The title is misleading, If not mistaken I agree, but the passages I quoted basically come from the text of the study. Once again, you failed to identify what is erroneous because you can't because you don't understand the study.

Moving on....

You failed to answer my question about your silly demand for identifying the process. The "process" (or lack thereof) already occurred (or did not) in the brains of these PD cadavers. Process isn't dynamic in a cadaver. Far from it. It has already taken place or it hasn't. A very, very, very simple fact.

Therefore, because they did not find structures resembling prion structures ( i.e. misfolded proteins or alpha-synuclein aggregates that are prevalent and seen in brains of animals and humans assaulted by infectious disease) when they examined the brains, the concluded (and rightly so), that the prion process did not take place in these PD patients.

Parkinson whether motor related or cognitive related is NOT a Prion Disease that upon the autopsy shows a prion process. They didn't find the protein alpha-synuclein inside the lowest part of the brainstem nor did they see anything resembling a "spread" upwards which usually occurs in a prion disease state.

PARKINSONS IS NOT A CONTAGIOUS DISEASE. NOT EVEN CLOSE!

Why?

Because the main proteins involved in Parkinson's disease pathology do NOT behave as a "prion".

S

[sunvox]

Thanks iq for bringing this interesting article to light. Honestly, I admit to being surprised by the hypothesis. Logically to me I would never have thought scientists would even consider the possibility of alpha-syn as being a prion even though it does have prion "like" behavior.

Bear, I sadly must agree with Sharon on this score. However, once again Sharon you just show yourself to be a most unpleasant individual in your online discourse. I wish you could find a way to tone down your condescension.

Sharon, I will disagree with one line you wrote:

"Propagation was not the central issue of this study contrary to your opinion it was necessary."

The entire point of the study and this discussion is whether or not alpha-synuclein is a Prion. What then is the scientific definition of a Prion?

-

"Prions are misfolded proteins with the ability to transmit their misfolded shape onto normal variants of the same protein." - en.wikipedia.org/wiki/Prion...

-

I know, I know, I hate quoting Wikipedia, but in this case the article is rife with scientific references that explain the real story, and the real story is that Prions are a theory in themselves that are often debated as is seen with this study. They also have slightly different definitions depending on what disease and which researcher is being examined or examining. In general though the whole point of Prion theory is "propagation". Prions propagate.

Bear, I think the part you are missing is that when alpha-syn aggregates it forms amyloid-beta sheets of a specific structure versus what is expected of prion pathology, and that is the highly complex issue that is at the heart of the research. How Prions propagate is the crux of prion theory as a protein wasn't supposed to be self propagating according to early cellular theory, but science found several just such proteins and struggles to explain how they propagate. What scientists have learned though is that when prions self propagate they take on a particular structure and that structure has only recently been discovered and available to be "seen" using the technology in this study. They did find cross-beta alpha-sy but not of the shape that should have been formed by prion behavior. Also it is important to note that the reason this even came up on scientist's radar is because alpha-sy clearly has "prion LIKE" behavior, and THAT drove the question as to whether or not it truly was a prion.

-

To me what is important to understand and what seems to be lacking in both your comments is that alpha-synuclein is still seen as the "bad boy" in Parkinson's. The question remains: why do people with Parkinson's have a toxic form of alpha-synuclein, but other people do not? In some cases, it appears to be genetic, but in other cases it remains a mystery. What I believe is not a mystery and what lies at the heart of my personal regimen and frequent discussion on HU, is my belief supported by the latest research that alpha-synuclein is toxic in people with Parkinson's because it forms an oligomer. The oligomerization of alpha-synuclein is the second derivative of the disease, but oligomerization of alpha-sy is likely the only common denominator and the one that science might actually have a chance at fixing by enhancing the bodies natural autophagic processes. Perhaps interesting or not this is actually counter to what the Japanese researchers seem to suggest in their public comments on the research where they hypothesize that it is the presence of aggregates that is toxic. That is for a whole other discussion, but suffice to say I disagree with that theory vehemently and think there is ample evidence to prove that it is not the aggregates that are toxic, but the oligomerization.

-

Here are several studies and articles that underly my belief:

ncbi.nlm.nih.gov/pubmed/295...

scienceofparkinsons.com/201...

ncbi.nlm.nih.gov/pubmed/294...

ncbi.nlm.nih.gov/pmc/articl...

and a Phase 2 clinical trial of a drug for the treatment of Parkinson's based on the theory of alpha-sy as a toxic oligomer:

prothena.com/pipeline/prx002/

Cheers,

Joe in NY

[park_bear in reply to sunvox]

Thanks, Joe, for your correction and edification. Agreed that the failure of autophagy is a key issue. I do not have a position on the aggregates vs oligomer debate. That said, one of the studies referred to in your SoP reference has this to say:

pnas.org/content/115/11/E26...

"We discovered the existence of a type of α-synuclein aggregate, smaller than previously described and conformationally distinct, that we called “pα-syn*.” Pα-syn* was present in neuronal cultures and mice brains injected with recombinant α-synuclein fibrils as well as in the brains of PD patients. We showed that pα-syn* is made of trimmed α-synuclein resulting from a failed cellular attempt to degrade fibrillar α-synuclein aggregates. We found that pα-syn* is a major neurotoxic species inducing mitochondrial damage, fission, and mitophagy, therefore constituting a central player in PD pathogenesis."

Your thoughts?

[sunvox in reply to park_bear]

Hi Bear -

Yes, I think Simon said it best:

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"But very recently the idea of oligomer versions of alpha synuclein causing all the trouble has became more complicated with the publication of this study."

-

My only thought on that research is that the researchers started by injecting "fibrillar alpha-sy aggregates" which then became the partially degraded toxic new aggregate species because of incomplete autophagy, so in terms of developing a treatment if one can stop the toxic oligomer from forming and clear it out altogether then presumably that would stop the formation of the toxic aggregates as well. Normal alpha-sy is a monomer and does not aggregate. It should not turn into either an oligomer OR a fibril, so the key still seems to be to recognize alpha-sy that is not a monomer and get rid of it - before it can oligomerize OR aggregate or worse both.

-

Although my disease, SCA1, is no cake walk either, I am frequently glad that I do not have Parkinson's because the more you learn the more you realize Parkinson's is an intensely complex disease that is not going to lend itself to simple solutions.

-

Joe