What we are up against. Parkinson's Pathology: Alpha synuclein. Lewy Body.

[park_bear]

Image credit: Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes biorxiv.org/content/10.1101...

Numerous genetic mutations can cause Parkinson's[1]. The most potent among them are mutations that cause alterations in alpha synuclein. SNCA is the gene that codes for alpha synuclein. Persons with extra copies of SNCA get young onset Parkinson's at successively earlier ages depending on how many extra copies of the gene they have[2]. They produce normal alpha synuclein, but too much of it. So even a mere excess of normal a-syn can cause Parkinson's. Complete lack of alpha synuclein is not good either as demonstrated by alpha synuclein knockout mice[3].

Alpha synuclein is a protein comprised of 140 amino acids. In addition to duplication, there are half a dozen mutations that cause amino acid substitutions and result in young onset Parkinson's[2]. A mouse has been genetically modified to produce one of these, human alpha synuclein with the A53T mutation: "A53T mutant mice develop intraneuronal inclusions, mitochondrial DNA damage and degeneration, and apoptotic-like death of neocortical, brainstem, and motor neurons. " [4]. (A53T = amino acid at position 53 changed from Alanine to Threonine).

Alpha synuclein can assume an impressive variety of different shapes (conformations), either singly (monomer) or in groups (oligomer). This includes helices, ribbons (beta sheets)[5], helix of paired ribbons (fibrils), spirals (Greek key) [6]. This increases the difficulty understanding the genesis of PD. See images in my comments below for examples.

When alpha synuclein aggregates into a mass known as a Lewy body, as shown in the image at top, the result is cellular impairment and potential death. We can see that the bulk of the Lewy Body is made up of alpha-synuclein, which forms the scaffold for the structure. We can also see that the mitochondria haplessly caught up in it are in the process of being digested by lysosomes, the cell's means of recycling.

It is not only mutations that cause development of Lewy bodies. A Swiss research team recently published this very thorough work tracking the creation and development of Lewy bodies[7]: "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. .... By extending the characterization of this neuronal seeding model from day (D) 11 to D14 to D21, we were eventually able to observe the transition from fibrils to α-syn–rich inclusions that recapitulate the biochemical, morphological, and structural features of the bona fide human LBs, including the recruitment of membranous organelles and accumulation of phosphorylated and C-terminally truncated α-syn aggregates "

It takes 3 weeks from inoculation with alpha-synuclein fibrils for Lewy bodies to form. (Which is why animal studies that pre-treat with a test substance prior to applying the toxicant are not modeling Parkinson's.)

"Overall, the sequestration of proteins related to the intracellular transport inside α-syn inclusions seems to result in an impairment in the trafficking of organelles and vesicles, such as mitochondria, endosomes, lysosomes, and the synaptic vesicles, that eventually accumulate inside α-syn inclusions... Interestingly, not only proteins involved in mitochondrial transport were enriched in the insoluble fraction of the PFF-treated neurons but also proteins related to mitochondrial dynamics, the mitochondrial apoptotic pathway, and the energy metabolism pathways... This indicates that the process of inclusion formation that occurs throughout D14 to D21 might dramatically alter mitochondrial physiology, suggesting that mitochondrial dysfunction could be a major contributor to neurodegeneration in PD and synucleinopathies."

"Strikingly, our transcriptomic analysis revealed that 156 genes involved in signaling pathways related to the regulation of neuronal cell death were also significantly changed over time in PFF-treated neurons ... These genes started to be significantly dysregulated at D14. At D21, 70 genes involved in cell death signaling pathways were up-regulated in PFF-treated neurons"

α-Synuclein is emitted by neurons, both healthy and unhealthy. In the latter case it becomes a source of transmission of pathological α-Synuclein:

"In healthy and pathological settings, both monomeric and multimeric forms of α-syn are detected in the blood plasma and cerebrospinal fluid. An in vitro study overexpressing human α-syn in differentiated SH-SY5Y cells revealed that a significant amount of α-syn was detected in the culture medium as early as two hours and had accumulated over time. The extent of multimerization of α-syn at both the intracellular and the extracellular environment is also likely associated with its expression within the cells. In cells expressing low levels of α-syn, only the monomeric form of α-syn was detected in both cell extracts and the conditioned medium. Studies using H50Q and A53T mutant variants also showed a significantly enhanced secretion of α-syn into the surroundings"

To reverse disease it would seem we need to get the accumulated α-syn in the Lewy bodies to dissociate and revert to monomeric form or to find a way to induce the affected cell to eject it.

Certain toxins are potent triggers that also get this process started. The focus on mutations in this post is meant to simplify this already complex discussion as much as possible. Parkinson's is almost certainly more commonly caused by toxins than by genetic defects.

References:

1. sciencedirect.com/science/a...

2. Autosomal dominant Parkinson’s disease caused by SNCA duplications sciencedirect.com/science/a...

3. α-Synuclein knockout mice have cognitive impairments sciencedirect.com/science/a...

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

5. Alpha-Synuclein Aggregation Pathway in Parkinson’s Disease:Current Status and Novel Therapeutic Approaches mdpi.com/2073-4409/11/11/1732

6. Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles link.springer.com/article/1....

7. pnas.org/doi/10.1073/pnas.1...

8. α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword mdpi.com/2218-273X/12/4/507

α-Synuclein preformed fibril (PFF) video: youtu.be/uz-FQrcU8XU?si=kYg...(Not working as expected?)

[park_bear]

Image credit: Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles

molecularneurodegeneration....

four distinct types of full length a-Syn fibril

[park_bear in reply to park_bear]

A substitution of a different amino acid at A53 due to mutation disrupts this conformation and causes young onset PD. Therefore, the ability to form this structure is likely a part of a healthy collection of alpha synuclein conformations.

Image credit: Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles

molecularneurodegeneration....

single layer within a mature αS fibril

[Gymsack]

What causes genetic mutations? Is this a common event

[park_bear in reply to Gymsack]

In the case of Parkinson's most genetic mutations are inherited, but that doesn't answer the question of how they arise in the first place. According to this article:

evolution.berkeley.edu/evol...

"The idea that errors in DNA repair are an important source of mutations that matter for evolution fits with many lines of evidence – including the evidence described here that the number of new mutations increases with the age of both genetic parents"

Additional detail at the link.

[fnedorez70 in reply to park_bear]

Pb- as a happy owner of 2 mutations and also having pd for 10 years I certainly understand the complexity of the numerous questions raised in this publication. I know with the certainly that my grandfather on my mothers side had Parkinson's disease. He had tremors and I don't. He lived to be 92. He used to smoke a lot. I never smoked. I guess he had one of the mutations I can reach this conclusion knowing the history of my family

😆

[JJAJJ]

I pressed ‘like’ 3 times but it registered ‘unlike’ Quite often does🤷‍♀️Anyway very interesting, thanks x

[park_bear in reply to JJAJJ]

That is normal. It is giving you the option to change your mind.

[Lyricist]

You are inspirational PB. Your writings and comments shed light on complex issues and help us PwPs to understand the path we are on. Life with PD is like climbing Helvellyn via Striding Edge without the confidence, balance and surefootedness of youth. I find this forum an invaluable source of optimism as we gain a greater understanding of our lot. Thank you.

[Pixelpixie]

I take this in hopes only helps:

cell.com/cell-reports/pdf/S...

[park_bear in reply to Pixelpixie]

Very interesting. is this the version you are taking?

amazon.com/Bio-Kult-Mind-Pr...

Notice any Improvement?

[Pixelpixie]

No, just straight probiotic. Smart brand

[MBAnderson]

While much of this is well above my pay grade my take away is that expecting one pharmaceutical to resolve every gene pathway is not likely (read; not going to happen.)

[park_bear in reply to MBAnderson]

That depends upon at which stage of the disease process one is seeking to intervene. IIRC there is a drug for the LRRK2 mutation under development.

[park_bear in reply to MBAnderson]

Annovis' Buntanetap is supposed to reduce alpha synuclein production, which has the potential to slow or even halt progression. I wish there were some positive anecdotal reports from the current phase 3, although halting progression would not be immediately obvious.

[WinnieThePoo in reply to park_bear]

There doesn't seem to be too much of that. Having spent 2 years on a trial for a monoclonal a-syn antibody, with no positive results, I find Milton Werners (Inhibikase) explanation persuasive. And if correct, it would explain why Buntanetap is not going to work.

In essence

Published in Science Translational Medicine, in January

"Showed that the mis-folded plaques (proteins) are internalised by the effected neurons, the disease is entirely internal to the neurons that are failing, and that's where you have to attack the disease. And when you do it that way, you drive recovery of function, you preserve the neurons from degrading, and you clear the protein pathology - you remove the plaques from the right compartment . Where they reside to cause the disease is within the affected neurons and that's where you have to attack it ...

AND AN ANTIBODY CAN'T GET INSIDE TO DO IT "

google.com/search?client=fi...

3 minutes :50

(nor can Buntanetap). This is partially acknowledged by Annovis in

outsourcing-pharma.com/Arti...

"KOL's expressed concerns about both products likelihood of success because it is still unclear whether targetting extra-cellular protein with Buntanetap ... will slow the progression of PD and offer enough other functional benefits"

[park_bear in reply to WinnieThePoo]

I agree that IkT-148009 has a lot more potential than Buntanetap.

With that said, I think the way they're running the phase 2 trial is a mistake. In the space of three months I expect very little progression in the placebo arm, and in very early stage patients not a whole lot of symptoms to relieve in the treatment arm. I will be impressed if they come up with significant results. In my opinion they should have accepted a bit later stage patients, and run the double blinded study for at least 6 months.

On the plus side they did demonstrate the right way to run an animal trial: healthunlocked.com/cure-par...

[WinnieThePoo in reply to park_bear]

risvodetinib as it is now called is my current favourite hope for a significant new therapy. (If it achieves its full potential it is very nearly a "cure"). I have read loads, and watched a lot of video's and could post links all day. I understand where you are coming from with the trials , but

1) Milton Werner does not strike me as a fool

2) The 201 trial is a 2 - 01 , a phase 2 trial, which is safety , tolerability and dosing. Not efficacy (although that will be of interest)

3) The trial criteria (including no medication) are identical to SPARK and Biogen had no problem filling that. There are 50000 new USA diagnoses - all unmedicated - each year. They are not going to struggle to find 300

4) Regarding trial design, any participant medication complicates analysis of results. Dr Werner is looking for his quickest route to market. Of the many videos I have watched and could link- this one explains why they think it is too inefficient to try to get authorisation for disease modification for PD, so they are going to try for symptom relief, and prove the disease modification in the field 57 minutes in, and particularly 59 minutes in shine some light on their thinking google.com/search?q=inhibik...

1 hour marker explains the phase 4 idea

[park_bear in reply to WinnieThePoo]

The current phase 2 may not officially be about efficacy, but I am pretty sure that a lot of people are going to be very interested in what it does have to say about efficacy.

Thanks for the link.

[MBAnderson in reply to park_bear]

Out of the dozen or so people on this forum in the trial only one reported benefit. It doesn't bode well.

[Gymsack]

So the penalty we pay for a fast evolution is instability in the genetic profile. Is this similar to the rate of change in other animals or are we once again different. The ability for a species to adapt quickly is beneficial in a changing environment and it would seem many other species were not so ably equipped but instability over an extended length of time of status quo environment could lead to a retrograde ,could it not ? Could we be evolving in the wrong direction.

[Adlon57 in reply to Gymsack]

We are 'meant' to be more intelligent than other animals, top of the chain🙄but with the aid of the likes of AI, have we reached a crossroad, with the likes of genetics and climate change, are we "evolving" in the wrong direction?

[Baron1]

Good Evening,

Your brief summation of the causation of neurological disorders attributed to alpha synuclein destruction, highlights the key facts that escapes most general practitioners.

They do not fully understand the gamut of what patients are up against, nor do they understand how to best treat the patient who presents with Parkinson's Disease.

The daily intertwining of cell information trying at best to survive is interrupted by a process that inflames and destroys cells functions and the the brain cannot deal with that on a level that it can suppress.

"Too many doors with not enough keys to open and lock when it comes to neurological disorders."

Thanks for the write up

[Likii]

Overwhelmingly, so-called "Parkinson's" is the result of variable exposure to environmental toxins and variable genetic capacities to handle this.

In simple terms: throw enough people into a toxic soup for long enough and some of them will become ill.

But there's no money in this explanation so fancy-pants "science" will continue to produce ever-more complex theories and therapies that won't really work because they don't address the main cause: a toxic environment.

[park_bear in reply to Likii]

You are right to point out the importance of the role of toxins and I've added language accordingly to the post.

[WinnieThePoo in reply to Likii]

That's because it explains nothing. Critically it fails to explain why most people in the toxic soup (99%) don't get PD

[Likii in reply to WinnieThePoo]

My post does explain that: variable toxin exposure and variable genetics.

It's as clear as the honey jar stuck on your nose, Pooh.

The toxic soup is not homogenous. Think of it as a minestrone with 100s of thousands of distinct toxins as ingredients. Each individual has a unique swim in the soup. This results in near-infinite combinations and permutations of individual exposures.

Add individual genetic capacities for coping with this unique toxic exposure and we can expect an enormous variety of outcomes. Some are lumped together in categories - such as "Parkinson's".

Hope that helps.

[WinnieThePoo in reply to Likii]

It may help you feel you are right but it's very unlikely to produce any tangible benefit anyone might call help

[LagLag37 in reply to Likii]

Are you really 126??

[House2]

pubmed.ncbi.nlm.nih.gov/374...

[jeffreyn in reply to House2]

"Binding modes of potential anti-prion phytochemicals to PrPC structures in silico"

Catch no ball.