Is Parkinson’s Disease a Prion Disease? Alpha synuclein and prion-like behavior.

[House2]

Prion diseases are a type of infectious disease transmitted by a self-replicating protein, the prion protein (PrP), and as yet are still not fully understood at the molecular level.

Cellular and molecular evidence of prion-like propagation in neurodegenerative diseases, the clinical relevance of their cell-to-cell propagation by 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. These studies discuss the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. 1

Debates on the importance of the role of prion-like protein aggregates in neurodegenerative diseases (ND) and  whether they are causal or a consequence of the disease, are also discussed.1

 The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as alpha Synuclein,  propagate their misfolded configuration by transforming their respective soluble monomers into fibrils. 1

 Parkinson's disease (PD) is characterized by the presence of alpha Synuclein inclusions in the brain and the degeneration of dopamine-producing neurons. There is evidence to suggest that the progression of PD may be due to the prion-like spread of  alpha Synuclein a protein related to the pathology of Parkinson's disease, that  shows  many prion-like pathogenic characteristics. 2    So understanding and limiting alpha Synuclein propagation has become  a key area of research for developing novel PD treatments. 3

 Significant evidence suggests that misfolded alpha-synuclein (aSyn), a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, inoculation of  mice with  human alpha Synuclein preformed fibrils (PFF) has promoted  Parkinson-like symptoms and deficits in these mice associated with  substantial spreading of pathogenic alpha-synuclein.8

 Lewy bodies  are round, reddish inclusions inside the body of the nerve cell and composed of an abnormally folded and aggregated protein called alpha-synuclein. 

 Alpha-synuclein is a 140-amino-acid protein divided into three regions with distinct net charges. 4

alpha Synuclein  also has a high propensity to aggregate to β-rich structures in a complex sequence of events which involves soluble oligomers and insoluble fibrils. 5

Under pathological conditions alpha Synuclein monomers become misfolded and  form insoluble, fibrils as well as neurotoxic oligomeric intermediates. 4

As a monomer, the protein is intrinsically disordered and only forms organized structure when it binds to other partners. Although its “true” function is unclear, it is linked to membranes by its association with synaptic trafficking and forms α-helical structures on  membranes. 5

Certainly, alpha Synuclein aggregation may not be the sole cause of dopaminergic neuronal loss, and our understanding of the complex interactions between the aggregates of pathogenic proteins and neurodegeneration continues to evolve. 6

Although Lewy Body pathology is not the only causative factor for PD, it is known that in the presence of alpha Synuclein oligomers and fibrils, neurodegeneration occurs.6

PD and Dementia Lewy Body share a similar pathological hallmark of alpha Synuclein aggregates throughout the nervous system including in the limbic, brainstem, and cortical regions of the brain. 7

Although alpha Synuclein aggregation is seen as a unifying and “central pathological change”, the complexity of these processes may be appreciated by the fact that different synucleinopathies show different clinical symptoms and affect different brain cells (neurons or oligodendroglia), leading to different types of intracellular aggregates (spherical Lewy bodies in PD, less structured glial cytoplasmic alpha Synuclein inclusions in Multiple System Atrophy). 5

Thus in practice there is a pathophysiological disease spectrum.

Even within PD itself, the disease can originate in different places, either brain-first (from which it can spread to the rest of the body) or body-first (where alpha Synuclein  aggregation starts in the gut and then transmits via the vagus nerve to the brain).5

The accumulation of pathological substrates like alpha Synuclein can precede the clinical onset of symptoms in patients by decades. Therefore, the early detection of misfolded protein accumulation may be used  to  facilitate a more timely diagnosis and more effective treatment.5

A significant reduction in alpha Synuclein aggregations with a corresponding increased preservation in dopaminergic innervation observed from in vivo (animal) studies, indicate a clear benefit of targeting alpha Synuclein in preventing the progression of  PD. Similarly, the positive outcomes from the clinical studies assessing the efficacy and safety of immunotherapies provide evidence of the potential viability of anti- alpha Synuclein therapies. 6

Therefore, treatments that target alpha Synuclein oligomeric and/or fibrillar species that are toxic to neurons may reduce neurodegeneration, but this therapeutic strategy has yet to be fully translated into efficacious clinical studies. 6

Even as human clinical studies of targeting alpha Synuclein lag, the evidence available on the effect of a therapy aimed at  oligomeric and fibrillar alpha Synuclein  and its interaction with dopaminergic neuronal activity suggest  that  alpha Synuclein should be a primary target to suppress  neurodegeneration in Parkinson’s Disease. Taken together the data in this review, provides compelling evidence  that alpha Synuclein  is a viable and promising target to limit alpha Synuclein contribution to the development and progression of  PD. 6

Exposure of cell to preformed recombinant alpha Synuclein fibrils induces the formation of visible aggregations within these cells, which could be characterized by using four indices: 1. The number of dots per cell, 2.  The size of dots, 3. The intensity of dots, and 4. The percentage of cells containing alpha Synuclein aggregations. The four indices proved to be reliable indicators of the effectiveness of interventions and therapeutic agents directed against alpha Synuclein propagation in a treatment screening model.

This simple and efficient in vitro model system can be used for high-throughput screening to discover novel therapies for inhibiting alpha Synuclein spread.3

A recent technique, the seeding amplification assay (SAA) is able to detect minute amounts of misfolded αSyn in the cerebrospinal fluid (CSF) by examining its ability to induce further aggregation of non-aggregated or monomeric alpha Synuclein.7

This alpha Synuclein Seeding Amplification Assay CSF biomarker was able to detect alpha Synuclein  in CSF of  confirmed D-Lewy Body and Parkinson’s Disease patients with a sensitivity of 92% and 95%, respectively, and a 100% specificity.7

These assays are also able to detect the accumulation of misfolded alpha Synuclein  in subjects with features of prodromal parkinsonism, such as isolated rapid eye movement (REM) sleep behavior disorder (IRBD) and pure autonomic failure.7  A positive result of alpha Synuclein Seeding Amplification Assay in IRBD cases was associated with an increased risk of developing PD and DLB at 2, 4, 6, 8, and 10 years of follow-up.7

References 

1.Hu C, Yan Y, Jin Y, Yang J, Xi Y, Zhong Z. Decoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases. Neurosci Bull. Published online September 27, 2023. doi:10.1007/s12264-023-01115-9

2.Cordeiro Y, Freire MHO, Wiecikowski AF, do Amaral MJ. (Dys)functional insights into nucleic acids and RNA-binding proteins modulation of the prion protein and α-synuclein phase separation. Biophys Rev. 2023;15(4):577-589. doi:10.1007/s12551-023-01067-4

3.Kim BJ, Noh HR, Jeon H, Park SM. Monitoring α-synuclein Aggregation Induced by Preformed α-synuclein Fibrils in an In Vitro Model System. Exp Neurobiol. 2023;32(3):147-156. doi:10.5607/en23007

4.Kamski-Hennekam ER, Huang J, Ahmed R, Melacini G. Toward a molecular mechanism for the interaction of ATP with alpha-synuclein. Chem Sci. 2023;14(36):9933-9942. doi:10.1039/d3sc03612j

5.Vasilevskaya A, Martinez-Valbuena I, Anastassiadis C, et al. Misfolded α-Synuclein in Cerebrospinal Fluid of Contact Sport Athletes. Mov Disord Off J Mov Disord Soc. Published online October 4, 2023. doi:10.1002/mds.29621

6.Rodger AT, ALNasser M, Carter WG. Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review. Int J Mol Sci. 2023;24(13):11022. doi:10.3390/ijms241311022

7.Peña-Bautista C, Kumar R, Baquero M, et al. Misfolded alpha-synuclein detection by RT-QuIC in dementia with lewy bodies: a systematic review and meta-analysis. Front Mol Biosci. 2023;10:1193458. doi:10.3389/fmolb.2023.1193458

8.Tullo S, Miranda AS, Del Cid-Pellitero E, et al. Neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy prior to onset of motor symptoms. J Neurochem. Published online October 7, 2023. doi:10.1111/jnc.1596

[park_bear]

Yes. see also: healthunlocked.com/cure-par....

"Recently, it was shown that exogenously added preformed fibrils (PFFs) of α-syn can act as seeds to initiate the misfolding and aggregation of endogenous α-syn, in both cellular and animal models, in the absence of α-syn overexpression."

[gomelgo in reply to park_bear]

could somebody please explain this in plain English?

[Baron1 in reply to gomelgo]

Good morning,

Simply put, there are a plethora of proteins in the body and all contribute to our existence. They are working hard to keep us all alive and well.

Alpha Synuclein is one of those, and they are like paper origami; they fold to a certain predetermined pattern to able to go about their duties.

Science has long shown that like all proteins they can get infected by viruses.

All humans can be carries of prions (misfolding proteins), and they are actually smaller than virues. More importantly because most humans consume meat, the meat are carries of prions, which when consumed from the meat enter the human who consumed the meat.

Viruses hijack the alpha synuclein and coerce them to fold a different way and create more or less a deformed protein and like say a zombie, they go about doing the wrong thing in your body. In the process they do exactly the same and coerce other alpha synuclein to fold their way and the process perpetuates.

When they start to appear in large numbers in the brain, they cause the neurotransmitters and synapse to fail and cause neuron-degeneration by causing the highway of information in the brain to be blocked like pot holes in a road or rubbish everywhere on the road, and signals in the brain can not get through, so cells dies.

This is a very basic explanation, so hopefully you start to understand how like seeds that you plant, the viruses get through the blood brain barrier or they are carried from the gut in cells (like a Trojan horse) and once in the brain, well its pretty hard to stop the prion propagating like seeds growing when science still do not have the medical drugs to stop the misfolding alpha synuclein.

Best wishes to better health my friend.

[gomelgo in reply to Baron1]

thank you very much for that explanation. It helps a lot, so how do we explain my PD diagnosis after 13 years being strictly vegan? I actually think that if this theory you propose is correct., That it may actually have been Covid that was infected with these prion, and spread throughout humanity over the last two years.

[park_bear in reply to gomelgo]

The correct translation into plain English is that once some errant alpha synuclein gets misfolded it can become a self reinforcing process that can continue to propagate. Viruses do not "hijack the alpha synuclein and coerce them to fold a different way". I suggest ignoring the prior comment which is nonsense.

[Baron1 in reply to gomelgo]

Good Evening,

It is great see that several people are trying to assist you, well done to all.

As you can tell from the varying comments, all have a differing opinion of what they perceive to be accurate in their belief of the subject matter that you requested clarity on.

Further to strengthening my position on "Virues" as one of the key players.

Neurodegenerative diseases (NDs) such as Alzheimer’s and Parkinson’s disease are fatal neurological diseases that can be of idiopathic, genetic, or even infectious in origin from viruses. The etiological factors that lead to neurodegeneration remain unknown but likely involve a combination of aging, genetic risk factors, environmental stressors, and viruses. The accumulating evidence shows an association of viruses with neurodegenerative disorders and suggests that virus-induced neuroinflammation and perturbation of neuronal protein quality control to be involved in the early steps of disease development.

Neurodegenerative diseases (NDs) are fatal chronic diseases of the central nervous system (CNS), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS).

As seen in alpha synuclein protein aggregation follows a nucleated polymerization process, in which misfolded proteins spontaneously coassemble into oligomers (nucleation) that reorganize into fibrils. These fibrils then act as seeds that bind and convert proteins of the same kind into their abnormal isoforms (seeding). Protein aggregation occurs sequentially in anatomically connected areas, suggesting a progressive spreading throughout the CNS of affected individuals.

Pathogens, and especially viruses, act as etiological factors in several NDs. An impressive number of studies highlights that viruses, through their capacity to hijack the host cell machinery and induce inflammation, trigger and/or contribute to degenerative processes. Viral infections can activate astrocytes and microglia or induce CNS infiltration by peripheral immune cells, thereby causing neuroinflammation. Some viruses can enter the CNS and affect neurodegeneration via lytic egress from infected neurons by impairing neuronal processes or by inducing neuronal apoptosis. Viruses can also directly contribute to disease-associated protein misfolding and subsequent processes of protein aggregate spreading.

Parkinson's Disease, the second most common ND, is characterized by the degeneration of dopaminergic neurons in the substantia nigra and the accumulation of α-Synuclein as Lewy bodies in neurons. Influenza-A, flaviviruses, and herpesviruses can induce acute or chronic Parkinson-like symptoms or post-encephalitic parkinsonism. Retrospective cohort studies reported an increased risk for developing PD after infection with hepatitis C and B viruses (HCV and HBV). Experimentally, mice infected with neurotropic influenza-A virus exhibit α-Synuclein inclusions in dopaminergic neurons as well as inflammatory processes and microglial activation. These α-Synuclein were shown to have changed form by way of the virus hijacking the protein and subjugating its form, which commenced the spread sequence across all neurons.

There are multiple studies, but it is up to each individual to garnish all the information they seem reasonable from their own research and establish your own belief as to what causes what and why.

Here in this forum I am glad each person can express their views openly.

Unfortunately, all have differences of what they constitute right or wrong, just as the science community have differing opinions. This is why we will never get a cure for most neurological diseases because all scientist think their studies or beliefs are correct and everyone else's are wrong.

[jeffreyn in reply to Baron1]

"Here in this forum I am glad each person can express their views openly."

It would be good if we had a way to tell if a person is really a person.

[gomelgo in reply to Baron1]

I have a lot of respect for everybody here. As well as a lot of empathy. But it's very hard to tolerate people calling other peoples words "nonsense". There is no need for that. Perhaps just say that you disagree, and explain why? We all can think for ourselves no?

[park_bear in reply to gomelgo]

I would prefer to think that but the number of recommendations that incorrect comment got makes me wonder.

Sorry but your scolding is not going to cause me to respect individuals that make up theories out of whole cloth and present them as fact. That is intellectually dishonest. It does not merit respect.

[park_bear in reply to Baron1]

Please cite a reference in a peer reviewed medical journal that says: "α-Synuclein were shown to have changed form by way of the virus hijacking the protein and subjugating its form".

[gomelgo in reply to park_bear]

Could you also do the same for your opinion that this is nonsense? Because I am convinced actually that my PD comes from COVID. I had a pretty severe early strain of it, and I keep thinking of this ncbi.nlm.nih.gov/pmc/articl.... I sadly have not had the time or energy to find more, but maybe others here have?

[jeffreyn in reply to gomelgo]

This SoPD blog post from Simon may be of interest.

scienceofparkinsons.com/202...

[gomelgo in reply to jeffreyn]

Thank you so much for sharing this. It is highly validating to me.

[gomelgo in reply to jeffreyn]

I also found this there, and it harkens back to my question/polling everyone to see if their tremors stop when asleep. scienceofparkinsons.com/tre...

[park_bear in reply to gomelgo]

It is not the business of medical studies to reject various individuals' incorrect pet theories. It is the responsibility of individuals making up theories to present evidence for them. Doubling down with AI generated blathering does not count as evidence. There's no evidence that viruses hijack alpha synuclein. It's possible to make viruses in the laboratory that cause defective alpha synuclein to be produced, but even for this there's no evidence that such a virus exists in the wild.

It is possible that covid triggered your PD. Alpha synuclein has antiviral properties. The covid may have triggered your body to overproduce it.

[gomelgo in reply to park_bear]

At one point in human history there was no evidence that hand washing was a way to fight germs. Your judgements and name calling are only taking away from your credibility in my eyes. And that is unfortunate.

[park_bear in reply to gomelgo]

That excuse could be used to justify any theory whatsoever. There's no justification for making something up and presenting it as established fact. If someone wants to present a new theory and say so that is another matter. I'm beyond caring what you think of my credibility at this point. I will not trouble myself to provide you any advice.

[jeffreyn in reply to park_bear]

I can see that protecting this forum from "AI generated blathering" is going to become more and more difficult.

[gomelgo in reply to park_bear]

No one is presenting anything as fact except you. They are postulating a possibility. Go back and read what you are responding to. you are calling something "AI generated blather" as though your ASSUMPTION about it is fact. Everyone is here trying to deal with suffering that is beyond repair. Maybe it's true that this is AI. But that could be just as true of anything. And if we start labeling things we don't agree with or don't like or wish to not be true, AI, then everything here possibly loses credibility.

"Cheers to all the people who can change their minds when presented with information that contradicts their beliefs". Jim Carey

And I will add cheers to all the people who are willing to even look at and question their own beliefs.

[park_bear in reply to gomelgo]

Now you are trying to tell me to take your erroneous word for what is in black and white: "Viruses hijack the alpha synuclein and coerce them to fold a different way".

What part of this is not being presented as a fact?

Now I am done with your nonsense.

[gomelgo in reply to park_bear]

Ok you live in your reality and I wil live in mine where everyone is allowed to question established beliefs. That is what science is to me, the art of questioning and being open to being wrong. The topic of this entire post is a question. You took parts of it out of context and proceeded to argue and make assumptions about the questioner. Pwp are hurting enough without being silenced by others. I hope we all learn to appreciate opinions and questions that don't necessarily match our own.

[jeffreyn in reply to gomelgo]

"Maybe it's true that this is AI. But that could be just as true of anything."

Not yet it's not, but I can see the day when it might well be, unless we do something about it.

We need a way to harness the knowledge base of this forum to counter the misuse of AI. Hopefully without the use of heavier moderation.

[MarionP in reply to Baron1]

Best basic explanation I think I have ever seen. But is alpha synuclein really more the cause, or result? Is it really resolved which one it is? And in any case, as it resolved to mostly be about environmental pollutants? I personally believe that environmental pollutants is the true cause, creates mutations in our dna, but I can't prove it. Meanwhile, whatever the cause, the locus of change is further downstream in any case, it is in DNA mutation. Great most of the research is coming to the conclusion that alpha sonucaan is in the cause chain, not the result chain although I think what happens is tomorrow's nuclean that is accumulated in the cell, you have a circularity there that just accelerates the pathology change, but introducing office of nucleon in the first place is what then triggers more and more and more cynuclean become distorted, somehow. Meanwhile the actual mechanism is down in your dna, but somehow is mutated. And to produce misfolded proteins means the mutation produces a consistent change, and then further accelerates and cycles from there. Ultimately it is the change of shape and sinuclean into the misfolded alpha synuclein and something changes more and more of them into that same misfolding. It's like a new highly persuasive religious figure introduced into a community, kind of like Christians in Rome, and finally somebody like St Augustine got convinced or found it easier to bend spines using it, and changed over the whole darn empire.

[SilentEchoes]

"Under pathological conditions alpha Synuclein monomers become misfolded and form insoluble, fibrils as well as neurotoxic oligomeric intermediates."

This answers the question: Is a-synuclein the cause or the effect? A-synuclein is the effect of a pathological process. Targeting a-synuclein does nothing to address the pathological process that triggered the protein misfolding in the first place.

When a diseased neuron dies it spreads it's toxic contents to nearby neurons. It's called auto induction. The initiation and spread of protein misfolding and aggregation is a key feature of disease etiology and progression.

Neuronal spread is what makes neurodegeneration a prion disease. Prions are definitely not viruses, they are composed solely of protein, without enclosed nucleic acid.

Neurodegenerative diseases are all Neuroimmune diseases, triggered by activation of microglia. This is what we need to target in treatment of neurodegeneration. There are multiple triggers for immune system activation - all of them are exogenous environmental toxins.

Our gut health plays a key role in our immune system. Gut dysbiosis makes us more vulnerable to toxic environmental insults.

Neuroimmune diseases are brain first, not body first. Reversing the disease state is incumbent upon healing the gut to strengthen the immune system.

The a-synuclein theory has been debunked. It was based on fraudulent research that originated at the University of Minnesota 20+ years ago. We need to move on.

Edit: I stand corrected. The research was on a different alpha beta oligomer - Aβ*56.

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

SE

[gomelgo in reply to SilentEchoes]

Brilliantly stated. Thank you for making this so much clearer.

[MarionP in reply to gomelgo]

Well brilliantly stated except for that last paragraph, which is actually really confusing and needs to be clarified and more better specified: when SE said "Edit: I stand corrected. The research was on a different alpha beta oligomer - Aβ*56." That changes the entire discussion and now it needs to be fully restated, entirely, because I don't know what the hell it means.

[park_bear in reply to SilentEchoes]

Please cite a reference in a peer reviewed medical journal that supports your allegation that alpha synuclein has been debunked as a cause of Parkinson's.

[Esperanto in reply to SilentEchoes]

The role of alpha-synuclein in these diseases is still an active area of study, and it is not accurate to claim that it has been completely debunked based on fraudulent research. It's important to approach scientific information with a critical mindset and consider multiple perspectives before drawing any conclusions.

[Baron1 in reply to Esperanto]

Well stated.

[House2 in reply to SilentEchoes]

α-Synuclein (aSyn) aggregation underlies neurodegenerative synucleinopathies. aSyn seeds are proposed to replicate and propagate neuronal pathology like prions. Seeding of aSyn can be recapitulated in cellular systems of aSyn aggregation.

Chlebowicz J, Russ W, Chen D, Vega A, Vernino S, White CL 3rd, Rizo J, Joachimiak LA, Diamond MI. Saturation mutagenesis of α-synuclein reveals monomer fold that modulates aggregation. Sci Adv. 2023 Oct 27;9(43):eadh3457.

[MarionP in reply to House2]

House: can you please try to restate and elaborate in common English please? I would very much appreciate it. That bit about aggregation is really frightening.

[park_bear in reply to SilentEchoes]

The reality is alpha synuclein has been extremely thoroughly validated and confirmed as the cause of Parkinson's. For example, half a dozen different mutations causing amino acid substitutions in the alpha synuclein protein cause different varieties of young onset Parkinson's. A couple of those including the A53T mutation have been bred into mice resulting in them exhibiting Parkinson's. Genetic mutations causing excess alpha synuclein also cause Parkinson's. Alpha synuclein has been found to be the major constituent of Lewy bodies, the key marker of Parkinson's pathology. There's really no doubt at this point that the alpha synuclein is the central feature of Parkinson's disease.

[park_bear in reply to park_bear]

Amino acid substitutions in alpha synuclein causing YOPD

Amino acid substitutions in alpha synuclein causing YOPD

[park_bear in reply to park_bear]

Locations of critical amino acids including some locations of substitutions in alpha synuclein causing YOPD

Locations of critical amino acids in alpha synuclein

[kaypeeoh in reply to park_bear]

We've had this argument before. In fact we were in the middle of it when I joined 3 years ago. A-syn is seen in PD. But is A-syn the cause or a result? So if you could pluck all the A-syn out of your body would you be cured? I use AHT, an old remedy for infectious and non-infectious diseases.

[park_bear in reply to kaypeeoh]

Mice that are genetically modified to not produce A-syn turn out to neurologically defective. So unfortunately, no we cannot do without it.

[parkie13 in reply to kaypeeoh]

What is it?

[kaypeeoh]

AHT? It is AutoHemoTherapy. I pull blood from a vein and quickly inject it into a muscle. youtube.com/watch?v=F3ZPpNS...(Not working as expected?)