Is the alpha-synuclein theory true? There is a bleak future of cure if it turns out to be false

[Farooqji]

This is because 90% of the trials focus on this theory

tmrwedition.com/2019/02/12/...

[ElliotGreen]

I think it's becoming clear that alpha-synuclein is part of the problem, but not the whole problem.

I think this 2017 paper in Science starts to bring several of the pieces together: oxidative stress (including toxic oxidation of dopamine), mitochondrial stress, and alpha-synuclein clumping.

science.sciencemag.org/cont...

[jimcaster]

I've been thinking about that a lot. Nearly all Alzheimer's treatments have been aimed at plaques in the brain, but there seems to be growing evidence that the plaques are a result and not a cause of Alzheimer's. I wonder if alpha synuclein builds up as the result of Parkinson's and not as a cause.

[ElliotGreen in reply to jimcaster]

Check this out:

This paper eventually consider "an intriguing hypothesis that α‐synuclein may be used by the cells as a natural scavenger of ROS" (ROS=reactive oxygen species).

YEAR: 2002

TITLE: Methionine oxidation inhibits fibrillation of human α‐synuclein in vitro

febs.onlinelibrary.wiley.co...

I was looking for info about methionine as a supplement, but methionine is an amino acid which is also a component of proteins, including α‐synuclein. In fact, there are four methionine's in α‐synuclein.

This paper was investigating what happens when the methionine in α‐synuclein get oxidized. 1) It turns out that methionine is very easily oxidized. 2) They found that α‐synuclein did NOT get clumped into fibrils when its methionine is oxidized. 3)

Moreover, the oxidation was reversible by an enzyme called MetO reductase (MSR).

Basically, the methionine "catches" oxidation in a way that protects other more important bits of the proteins (protecting the integrity of α‐synuclein and potentially protecting other proteins, too). They reference another paper from 1996 called "Methionine residues as endogenous antioxidants in proteins."

The main paper I've been discussing (the 2002 paper) finishes with this:

"It has been shown recently that exposure of mice to the herbicide paraquat causes upregulation of α‐synuclein, giving rise to the idea that increased expression of α‐synuclein is a part of a neuronal response to toxic insult 56. This observation, together with the potential protective role of methionine, leads to an intriguing hypothesis that α‐synuclein may be used by the cells as a natural scavenger of ROS. This may keep α‐synuclein from irreversible over‐oxidation, but at the same time may protect any oxidizable proteins present in the α‐synuclein microenvironment, and may also protect against lipid oxidation. Most importantly, the proposed α‐synuclein scavenging system, which may protect α‐synuclein from over‐oxidation, is dependent upon the effectiveness of the MSR system to continually recycle the oxidized methionine residues. We assume that the efficiency of the MSR system in the substantia nigra of healthy vs. Parkinsonian brains may differ. Of potential relevance in this regard is a recent report indicating a decline in the activity levels of MSR in various regions of the brains of Alzheimer's patients 57. Thus, impaired MSR function may represent an additional risk factor favoring the development of PD."

[ElliotGreen in reply to ElliotGreen]

In short, I think α‐synuclein may be there to protect against oxidative stress, but that when it gets messed up, it may become another problem.

[MBAnderson in reply to ElliotGreen]

By "messed up" do you mean once it gets upregulated by a toxic insult, becomes an overreaction?

[ElliotGreen in reply to MBAnderson]

Maybe. But I think not. I don't think that really describes what is going on. That makes it sound like some kind of auto-immune response. I think there are other specific things happening.

Bear in mind, the idea that alpha-synuclein serves as an antioxidant for other proteins is SPECULATIVE.

1) MAYBE (more speculation) when the protective methionines on alpha-synuclein get oxidized, and then other parts of alpha-synuclein get oxidized on top of that, then problems start happening?

(What causes alpha-synuclein to clump in the first place?)

2) See the comment I just added to the bottom of this post about Parthanatos gets activated in response to alpha-synuclein clumping. PAR sugars are released, and they make alpha-synuclein clumps more toxic.

[Rhyothemis]

There's a lot of work done on dysfunctional microglial activation, which is downstream of a-syn clumping. MCC950 appears to be effective in controlling microglial activation and was found to reverse Parkinson's symptoms in two mouse models. Unfortunately, there appear to be differences in the immune systems and neurobiology of mice and humans such that many drugs for various neurodegenerative diseases that show promise in mice don't pan out in human trials. Still, MCC950 looks particularly interesting, and since the target is neuroinflammation, it may work for other neurodegenerative diseases besides PD.

The big problem with MCC950 is that it is off-patent so no one is going to fund human clinical trials for it. Researchers are trying to develop a patentable derivative...

genengnews.com/news/parkins...

"They state that while lapsed patent issues mean that MCC950 won’t itself represent a commercially viable therapeutic candidate for treating PD, improved follow-on compounds have been developed that could be taken into the clinic for treating neurodegenerative diseases. "

[ElliotGreen in reply to Rhyothemis]

What is a microglial?

[Rhyothemis in reply to ElliotGreen]

Microglia are brain cells that support neuron function. They have a role as immune cells and are considered functionally to be the resident macrophages of the brain. Macrophages are part of the innate immune system, a first line of defense against pathogens; innate immune responses are not as specific as those of the adaptive immune system, which uses antibodies to target pathogens. In addition, microglia are the garbage collectors of the brain - they take up and digest intracellular debris that can result from things like traumatic brain injury. Microglia also play a role in the formation of synapses between neurons, and thus are important for learning and memory. They can become hyperactive - spewing out inflammatory molecules unnecessarily and damaging neurons and other brain cells such as oligodendrocytes (the ones that deposit myelin).

Mitochondrial function plays a role in determining the activation state (called polarization) of microglia. If mitochondrial function is compromised and the mitochondria start producing a lot of reactive oxygen species, for example due to exposure to rotenone which inhibits complex I of the electron transport chain, microglia can become hyperactive. Inflammation can also feed on itself in a vicious cycle. Part of the innate immune system response is the generation of reactive oxygen species, which is meant to harm invaders; unfortunately, if control mechanisms are compromised, the cycle of reactive oxygen species generation-inflammation can continue unchecked. Repeated head trauma is another situation which can cause a cycle of prolonged inflammation and can predispose one to developing PD, as molecules in damaged tissue (damage associate molecular patterns, DAMPs) also promote microglial activation.

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

You might ask (or maybe you have stopped reading already), what are these control mechanisms that are so crucial to limiting the cycle of inflammation? One is regulatory T cells, Tregs, a part of the adaptive immune system. As we age, the adaptive immune system becomes less effective. In part this is due to thymic involution, though T regs mature in the peripheral lymph nodes. You will note that the incidence of PD increases with age and is considered to be a disease of aging. Thus one could view the true cause of PD to be aging. Some would go further and argue that aging is itself a disease and that if aging can be cured then the diseases of aging would not exist.

youtube.com/watch?v=8iYpxRX...(Not working as expected?)

[Rhyothemis in reply to Rhyothemis]

All that and I did not even mention alpha synuclein - which is most definitely in the causal chain.

Here's a good talk on a-syn oligomers and microglial activation:

youtube.com/watch?v=vZCn4BN...(Not working as expected?)

[MBAnderson in reply to Rhyothemis]

I get an error message for the 2nd video.

[Rhyothemis in reply to MBAnderson]

Link fixed (I hope)

If not, the video title is:

Microglial Activation: Understanding Neuroinflammation’s Origins

on Sigma-Aldrich's YouTube channel

[MBAnderson]

Excellent article. I've read several of which make the same point recently. jackedmonstons posted this link yesterday Which makes the same point, that being, the way they're conducting PD, ALZ, ALS, research is destined to fail.

They make a compelling case.

fortune.com/longform/alzhei...

"Others, however, see the same data points—hundreds of billions of dollars spent, countless hours of human effort, tens of thousands of patients in ineffectual trials—and see a failure of the drug development process, starting in the academic research institutions. “The problem is the way science is done and funded,” said Zaven Khachaturian, editor-in-chief of trade journal Alzheimer’s & Dementia who formerly directed Alzheimer’s research across the National Institutes of Health, during one of several long phone calls. “It’s populated by people who follow the orthodoxy. To get continuous support, scientists must follow existing orthodoxies. Everybody says they value the individual or the maverick, but nobody will fund them because they say it’s a fishing expedition.” Research has shown that evaluators on panels that award government funding to scientists at research universities regularly give higher scores to conservative proposals than to those trying to break new ground.

"

"The ultimate cost, of course, is that we are no closer to curing Alzheimer’s than we were 20 years ago. Alzheimer’s still looms as a kind of living death for so many of us. One of every two people over 85 gets the disease, and since Alzheimer’s patients don’t develop new memories, its onset seems like a premature termination of the experience that is supposed to give meaning to our final years. “If you look at this as a public health issue, in terms of are we solving the problem of reducing the disability of patients, we haven’t made a dent,” said Khachaturian, the Alzheimer’s & Dementiaeditor. Since the beginning of this century, annual deaths from heart disease, stroke, and HIV have gone down. Annual deaths from Alzheimer’s disease have increased by 89%. As I was told several times while reporting this story: “Nobody knows an Alzheimer’s survivor.”"

L-Serine worth a look

[ddmagee1 in reply to MBAnderson]

A very sobering analysis (fortune.com - article ).

[Rhyothemis in reply to ddmagee1]

The reporting was quite lacking - they did not do adequate fact checking. BMAA is not present in the brains of AD patients:

β-methylamino-L-alanine (BMAA) is not found in the brains of patients with confirmed Alzheimer’s disease

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

~

Amyotrophic lateral scerosis (ALS) patients have been doing their own n=1 experiments with l-serine for several years; it is a readily available OTC supplement in the US and it has been known for some time that BMAA exposure is a risk factor for ALS , though I don't think it has been established what percentage of sporadic ALS cases can be attributed to BMAA exposure.

Here's a thread on l-serine in an ALS forum:

alsforums.com/forum/general...

~

As far as the amyloid hypothesis goes, I don't think anyone can say that beta amyloid is not involved in the causal chain (more like a web) in the development of AD [as is the case with alpha synuclein and the synucleinopathies]. However, there are legitimate criticisms of its utility as a target for therapies. Here is an informed debate on the topic:

youtu.be/intFXUJ2lfk(Not working as expected?)

The comments by the Teva representative were quite interesting.

~

As far as the 'root cause' of most neurodegenerative disease goes - the root cause is aging itself. If Fortune wants to do a really interesting article (if they have not done so already) they should do one on senolytic therapies, currently the most promising area of rejuvenation research. A number of biotech startups are investigating senolytics, of these, Oisin is particularly innovative:

youtu.be/pVBq5rCfomQ(Not working as expected?)

[MBAnderson in reply to Rhyothemis]

Do you take L-serine or Quercetin?

Would you share your regimen?

[Rhyothemis in reply to MBAnderson]

hmmm... my regimen is currently under re-construction as my body has decided to go up in flames this past week and I don't know why; I have a lot of problems with inflammation, which is probably why I tend to focus on it. The symptoms that brought me to this form have been mostly autonomic (orthostatic hypotension), as well as sleep issues (insomnia, short cycles, waking up with self-inflicted scratches on my arms, talking) and constipation. No diagnosis (not sure I want one), but I suspect MSA or pure autonomic failure.

I don't take l-serine or quercetin. Some people in the life extension community are doing their own DIY senolytic treatment with dasatinib and quercetin; I worry about long QT syndrome with dasatinib. I might consider the high dose fisetin thing, though.

fightaging.org/archives/201...

I've had some success with MitoQ - it fixed the orthostatic hypotension and the constipation. I've had some improvement in sleep recently - not sure if that is due to MitoQ or other supps. I take turmeric extract plus piperine (Gaia Herbs) in the am and Theracurmin in the pm, vitamins E & D, I cycle PQQ, vitex (trying to delay menopause as long as possible), sometimes CBD oil. Exercise, intermittent fasting, broccoli sprouts, natto, green tea, slow carb-veg heavy diet - pretty much everything on Rhonda Patrick's YouTube channel. For a while there, it was working.

For my latest bout of inflammatory mess I've been trying EGCG and d-mannose. D-mannose is often used for UTI's; I had some left over from a UTI a few years ago. Then I remembered that it can upregulate Treg function:

ncbi.nlm.nih.gov/pubmed/287...

Maybe just a coincidence, but the Still's Disease-like rash on my hands and forearms has resolved (my temp was only ~99.7, so not Stills? idk). The 'aches and pains' - as my mother called them - persist.

Maybe I'll post on d-mannose since I think it could help at least with UTIs in MSA patients.

[MBAnderson in reply to Rhyothemis]

Good videos. Thanks.

Well, I hope you have Parkinson's. (Never thought I'd say that -- but only if the choice is between those 3.)

[YoungPSP in reply to Rhyothemis]

Which MitoQ product do you use for orthostatic hypotension and constipation? I am currently being re-evaluated for possible MSA diagnosis and I struggle with both issues.

[ElliotGreen]

We should link to park_bear's post here from a month ago:

HU POST: Mechanism by which Alpha synuclein causes neuronal cell death found

healthunlocked.com/parkinso...

NEWS ARTICLE: Road to Cell Death More Clearly Identified for Parkinson’s Disease

hopkinsmedicine.org/news/ne...

SCIENTIFIC ARTICLE: Poly(ADP-ribose) [PAR] drives pathologic α-synuclein neurodegeneration in Parkinson’s disease

science.sciencemag.org/cont...

1) There are at least 3 different pathways by which cells are *programmed* to die. The relevant one here is

"Parthanatos, [...] a key driver of nerve cell degradation that is a marker of Parkinson’s disease. It is distinct from other known forms of programmed cell death such as apoptosis (a normal part of growth and development) and necroptosis (generally cell death due to disease or injury)."

2) Alpha-synuclein accumulation and clumping leads to Parthanatos.

"The first step down Parthanatos in Parkinson’s disease is the accumulation of misfolded proteins in brain neurons. These proteins, known as alpha synuclein, have long been linked to Parkinson’s disease progression, but it was unclear how they specifically affected brain cells."

3) In Parthanatos, a protein called PARP1 gets turned on, and this somehow leads to cell death.

When scientists *prevented* PARP1 from turning on, the cells were protected!

4) PARP causes neurons to create a sugar called PAR, which binds to alpha synuclein.

5) PAR increases the rate at which the alpha synuclein proteins clump together AND it makes the alpha synuclein more toxic.

[MBAnderson in reply to ElliotGreen]

Good information.