Parkinson's disease

#1059

Genetic interleukin-6 receptor blockade, chronic disease risk, and longevity: results from the women’s health initiative

#1060

See details at;

Japan approves stem-cell treatment for Parkinson’s in world first | News | djournal.com Japan approves stem-cell treatment for Parkinson's in world first

#1061

Dairy and Milk Intake and Risk for Parkinson’s Disease in Women and Men: A Systematic Review and Meta-Analysis 2026

Results revealed a sex-specific effect of dairy intake, a significant association with a higher risk of Parkinson’s disease in males (HR 1.28, 1.05-1.56), whereas no association was observed in females (HR 1.02, 0.80-1.30). For milk intake only, estimates were 1.36 (0.97-1.90) for males and 1.19 (0.94-1.51) for females.

1 Like
#1062

Irgm1 Promotes Microglial Clearance of α-Synuclein via the TFEB-Dependent Autophagy- Lysosome Pathway in Parkinson’s Disease 2026

:warning: Preprint + China + Tier 2 university + mice cell model :warning:

rapamycin restored TFEB nuclear translocation, reactivated the ALP, accelerated α-syn clearance, and abolished the increased toxicity of Irgm1-deficient microglia toward cocultured SH-SY5Y neurons after PFFs preexposure

#1063

Yeah, I guess. But the point is prevention of the conditions leading to alpha-synuclein misfolding in the microglia in the first place. By the time disequilibrium in calcium homeostasis appears it’s already too late (why I pay attention to calcium channels) - inflammation is downstream from this. I keep reading about how misfolding spreads prion-like, but the real crux is why the misfolding happens in the first place. The misfolding doesn’t just happen, it’s triggered. To be honest, I’m not impressed, sorry.

Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction

https://www.nature.com/articles/s41419-023-05672-9

“Abnormal forms of α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder”

Older illustration:

Bent out of shape: α-Synuclein misfolding and the convergence of pathogenic pathways in Parkinson’s Disease

1 Like
#1064

My guess is the misfolding arises from changes in splicing.

chatGPT says

#1065

Also

Chat GPT:

Yes, it is plausible, but not as a simple universal rule.

Reduced histone acetylation can alter alternative splicing because chromatin state affects how RNA polymerase II moves through a gene and how splicing factors are recruited to nascent RNA. In general, histone acetylation tends to open chromatin, while reduced acetylation tends to make chromatin more compact and can change exon recognition during co-transcriptional splicing. That general chromatin–splicing link is well established.

The important caveat is that the effect is context-dependent. Reduced acetylation does not always mean “more aberrant splicing” in exactly the same direction for every exon. Some exons are promoted by slower elongation and tighter chromatin, others are skipped; the outcome depends on the local gene architecture, splice-site strength, recruited chromatin readers, and which splicing regulators are present. Reviews of the field consistently describe histone marks as part of a combinatorial “splicing code,” not a one-way switch.

So for the SNCA / α-synuclein isoforms discussed above, the careful answer is: reduced histone acetylation could contribute to aberrant splicing in principle, but I do not see strong direct evidence from these sources that reduced histone acetylation is an established primary driver of the specific SNCA splice isoforms linked to α-synuclein misfolding. The SNCA literature more clearly supports altered splicing itself and altered chromatin regulation of SNCA expression, while the direct bridge from histone hypoacetylation → specific SNCA isoform shift → misfolding remains less firmly demonstrated.

There is also an interesting bidirectional possibility: α-synuclein pathology may itself feed back on chromatin. Reviews cite work showing nuclear α-synuclein can inhibit histone acetylation and promote neurotoxicity, which raises the possibility of a vicious circle in which misfolded or overabundant α-synuclein worsens chromatin regulation, potentially including splicing regulation indirectly. That is biologically plausible, but still not the same as proving that reduced histone acetylation was the initial cause of the splice abnormality.

So my bottom line is:

Reduced histone acetylation is a credible upstream contributor to aberrant splicing, including potentially the splice-isoform changes relevant to α-synuclein biology, but it would be too strong to say it is likely the sole or proven cause of the SNCA aberrant splicing above. A better phrasing would be that it is a possible and biologically well-motivated modulator.

I can also set this out as a step-by-step mechanism from histone hypoacetylation → polymerase kinetics/chromatin readers → exon skipping/inclusion → α-synuclein isoform balance → aggregation risk.

#1066

And speaking of alpha-synuclein formation, based on the calcium channel pathway, there’s this extremely speculative look (bathroom reading):

The Role of Magnesium in Parkinson’s Disease: Status Quo and Implications for Future Research

2 Likes
#1067

@CronosTempi can you please expand on the below?

(fwiw when I tried Mg threonate it gave me skin rash and I chose to stop and threw it away. Retrospectively, that was maybe a positive sign of it acting or “clearing an infection” as @John_Hemming would say?)

2 Likes
#1068

First, let me restate again - that list is based on speculation, mostly because of desperation: the research moves so slowly (to my eyes!) and the need is so urgent, that out of desperation I am forced to speculate and go out on a limb, taking chances which may not pan out. One general remark - some of the speculative agents may not work, not because they’re not useful, but because they need other things to allow them to work. PD (or any complex pathology) has so many systems go wrong, that you need multiple steps to fix things. For example, dietary copper doesn’t work against PD, but that’s because of other steps that need to be taken, and so you frequently get the effect of something being simultaneously in excess (copper) accelerating alpha-sinuclein formation and deficit blocking critical enzyme formation depending on tissue location.

Copper Ions and Parkinson’s Disease: Why Is Homeostasis So Relevant?

Re B1/B2. I was thinking of benfotiamine.

The Beneficial Effects of a Combination Therapy of Oral Benfotiamine and Methylcobalamin in the Treatment of Parkinson’s Disease: Case Reports and Review of the Literature

Here I was trying a multistep approach - not focusing on a single compound like magnesium or B1 or astaxanthin etc., but on a hopefully synergistic effect. So, for example since there is an issue with magnesium getting into the brain, you need to find ways of assisting that process by taking in other compounds - there is the hypothesis that magnesium deficit in the brain is an issue of transporter malfunction. Fix or get around that by other compounds, and all of a sudden magnesium makes sense, where magnesium by itself may not have seemed sensible.

I keep seeing papers to the effect “compound X works/does not work against PD”. I am very tired of this. Clearly that’s not how you should approach the problem. It’s like looking at a ladder with multiple broken steps and you call in a bunch of engineers and they deliver to you a report like Engineer A “fix step #6”, Engineer B “fix step #9”, Engineer C “fix step #12” and so on. It’s nonsense. You must fix ALL the steps or you can not climb up the ladder! PD is a ladder with many, many broken steps. It wil require many things. You can’t look at a screw (f.ex. astaxanthin) and say: this will not allow you to climb up the ladder (fix PD) - no, but the screw can be used to fix one of the steps and be part of the solution. By itself it may do nothing. In concert with other measures it will be part of fixing the ladder.

Again apologies for desperation speculation - but that’s all we have with such sloooooow pace of research - CAUTION: Chinese paper, shit model (mice with induced PD by MPTP injections :roll_eyes:)

Benfotiamine protects MPTP-induced Parkinson’s disease mouse model via activating Nrf2 signaling pathway

So, astaxanthin to me is not in the context of generalized lowering of inflammation, but specifically the Nrf2 pathway. Again, apologies for mice model - desperation speculation :cry:

Astaxanthin-loaded brain-permeable liposomes for Parkinson’s disease treatment via antioxidant and anti-inflammatory responses

Astaxanthin is neuroprotective in an aged mouse model of Parkinson’s disease

Astaxanthin suppresses endoplasmic reticulum stress and protects against neuron damage in Parkinson’s disease by regulating miR-7/SNCA axis

Astaxanthin as a Modulator of Nrf2, NF-κB, and Their Crosstalk: Molecular Mechanisms and Possible Clinical Applications

Magnesium - that is correct: elevated serum levels are the result of malfunctioning transport mechanisms. That is a frequent phenomenon - some substance is elevated in blood precisely because of defects in tissue absorbtion, therefore serum levels do not reflect tissue levels and you can actually have a deficit in the tissues. The issue here is that the magnesium doesn’t get into the brain efficiently, therefore elevated serum or CSF levels don’t help. The idea is that the threonate form can more easily get to the brain, especially if we assist it with other compounds.

Re: tributyrin. Direct tributyrin gets around the frequent problem in PD of poor microbiome profile and gut wall integrity.

Dietary tributyrin supplementation in Parkinson’s disease: An open-label target engagement study

Yet again: this is extensive speculation. My idea is to take a target, such as for example substantia nigra necrosis, look at all the steps leading up to it, and systematically attempt to repair or get around each step (like fixing all the steps on a ladder) using many compounds at once. Of course, this is very hard because there is still a ton we just don’t know - what exactly is the etiology of various pathologies in different ways PD presents. But you gotta start somewhere and I refuse to wait while research is moving at a snail’s pace. YMMV.

2 Likes
#1069

Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders

https://www.nature.com/articles/s41583-026-01032-6

#1070

Yes, of course. I’m still skeptical. Hundreds/thousands of people with PD are taking that combo, and I don’t think much progress has been seen (besides that anecdotal report). Laurie Mischley has a database of her patients, including what they supplement with and their symptom scores. I assume she would have found it if the combination was working. See for individual compounds: https://www.mdpi.com/2072-6643/15/4/802 with some signal for homocysteine factors and high dose thiamine (oral), so you might argue the combination could be even better, ofc.

OK for serum levels, but you think that’s also the case for CSF levels?

(Still, I’m convinced that calcium homeostasis plays a role. CCB users have a lower rate of PD in a dose-dependent way. The isradipine trial failed a genetic stratification might explain the failure. Some are also now trying intra-nasal isradipine.)

There are hundreds of papers reporting that a compound shows some benefit in a model (or even in patients) + a good rationale for its mechanism of action. For instance, I was about to post this one (before reading your reply): The anti-diabetic drug acarbose modulates the nucleation dependent amyloid fibrillation of wild-type α-synuclein 2026

Every year, the world’s best PD researchers & charities gather to review those compounds and prioritize which ones should go to trial: The International Linked Clinical Trials (iLCT) programme - Cure Parkinson's

I attended last year. It’s very frustrating because there are dozens of such compounds. After years of failing to find anything meaningful (although I think they’re onto something with GLP-1RA), they’re not focusing on combinations: Combination therapies: a change in approach for Parkinson’s research - Cure Parkinson's

But combinations might fail as well. We don’t even know if Parkinson’s is a disease. It might just be syndrome, a collection of people with similar symptoms.

2 Likes
#1071

FYI @CronosTempi I find this community useful to find anecdotal evidence/signal: https://healthunlocked.com/cure-parkinsons

29,375 members, I assume the vast majority of them with PD (and the rest caring for someone with PD). Simple queries:

  • “threonate”: 61 posts, latest 15 days ago, oldest 9 years ago
  • “benfotiamine”: 48 posts, latest 2 months ago, oldest 9 years ago
  • “methylcobalamin”: 26 posts, latest 16 days ago, oldest 10 years ago

So people are trying. And not reporting many benefits.

4 Likes
#1072

One more thing, and I will stop spamming: Mg threonate became popular in the mid 2010s. Magtein was launched in 2012. This Tier 2 Chinese paper found benefits in a rodent model of PD (MPTP) in 2019. 6y later: nothing more. So if dozens of random people are discussing the potential of Mg threonate for PD, surely some researchers are considering it as well. Maybe they’re trying it on a single mouse in their lab, see nothing, give up, and never publish anything. I might be wrong, but I feel like the lack of subsequent publications is a bad sign. The next logical step for the Chinese team that reported a positive result in the MPTP model would be to test it in another rodent PD model (transgenic, α-synuclein, 6-OHDA, mitochondrial dysfunction, etc.) or in another species (C. elegans, zebrafish, etc.) or for another disease (esp. Alzheimer’s). Of course there’s not much money in science to test supplements and other non-patented compounds but researchers want citations, so you have something that seems to work, isn’t it an easy win to try it on another model? Also, Mg Threonate is partially patented via Magtein so the “no one will make money here” argument is weaker. So I’m skeptical…

3 Likes
#1073

FYI, @CronosTempi: I’m told the main author is not reliable.

2 Likes
#1074

That’s disappointing. But this is a review, so how much can they screw up - I guess you have to follow all their references to see if they are distorting things; that’s a lot of work just to look at case reports. In general, the benfo excitement has kind of died down a bit. About 16 months ago I heard some rumors that people in Japan have been looking at benfotiamine and PD, but then nothing happened since. But like I said before, I’m very tired with papers that focus on a single molecule. No single molecule is going to “solve” PD, and constantly reading papers with such “findings” just makes me feel hopeless. We need a comprehensive approach starting with fundamentals, otherwise PD will turn into another “cure cancer” dynamic with no end in sight. So, some time ago I decided to just select one area and do a deep dive as far as I possibly can without having a lab. I want to become actually “specialist” (at least by absorbing the literature), in that one part. I selected calcium handling, because it seems to be such a basic part in NDDs in general.

Insofar as single molecules, I try to look at the broader context. For example, I am now convinced that statins are actually a negative for PD. But why? First you have disentangle the effect from the mechanism. The effect is lower LDL (or ApoB) - is that part of the chain? Or is it the mechanism of statins that’s the issue. Focusing on mechanism, as an example, I posted a study about how pitavastatin compared to other statins doesn’t deplete plasma CoQ10. If statins in general deplete CoQ10, is that going to factor into why they’re bad for PD? So it’s not just focusing on a single molecule - as an example of such:

Coenzyme Q10 and Parkinsonian Syndromes: A Systematic Review

So, would that mean that say, pitavastatin - unlike other statins - might not be a PD negative? There’s not enough in the literature to determine much. Exposure in early stages of PD (including before any symptoms), full blown PD, early onset vs late onset.

If you look at supplementing with CoQ10, this doesn’t do anything for PD - but what about supplementing for people who take statins? That has generally been underwhelming too.

So CoQ10 levels are lower in people with PD - but what do we do with that information? That’s the problem with single molecules being measured - because serum CoQ10 levels in PD are normal (or close to), the depletion is in various tissues, lympocytes etc. You don’t know why levels are lower in those tissues - is it downstream of some pathology, is causative itself or merely a marker etc. - that’s why I was interested to see if pitavastatin would exacerbate PD as well, since it doesn’t affect CoQ10 as much, but that’s again a tissue vs plasma thing. If you want to see how crazy these effects are of various statins, look at this (rat) study (free paper):

Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on ubiquinone levels in rat skeletal muscle and heart: relationship to cytotoxicity and inhibitory activity for cholesterol synthesis in human skeletal muscle cells

“This study sought to evaluate and compare the cytotoxicity of statins (cerivastatin, pitavastatin, fluvastatin, simvastatin, atorvastatin and pravastatin) in cultured human skeletal muscle cells (HSkMCs) and the effects on ubiquinone levels in statin-treated rat skeletal muscle and heart. Cerivastatin, the most potent inhibitor of HMG-CoA reductase, showed the strongest cytotoxicity (over 10-fold) among the statins examined, while the effects of the others were in a similar range. In rat experiments, neither pitavastatin nor cerivastatin decreased ubiquinone levels in skeletal muscle, but both dose-dependently lowered ubiquinone levels in the heart. As the rates of reduction by pitavastatin (9.6% at 30 mg/kg) and cerivastatin (9.7% at 0.3 mg/kg) were almost equal, it was estimated that cerivastatin reduced ubiquinone levels in the rat heart approximately 100-fold more strongly than pitavastatin, based on the effective doses. We found that cerivastatin showed the most potent cytotoxicity in HSkMCs and strongly lowered ubiquinone levels in the rat heart.”

So, CoQ10 levels in skeletal muscle tissue (where people complain about myalgia) were not affected by either cerivastatin or pitavastatin, both lowered levels in the heart, but cerivastatin reduced levels 100-fold more strongly than pitavastatin dose effectively?! And cerivastatin was vastly more cytotoxic.

Bottom line, you have to measure the levels of any single molecule in every tissue and you might find that the effects even in the same class of medications (say, statins), to be dramatically different.

Anyhow, it’s nice to come up for air from all these mechanistic studies and into the calm waters of outcome studies, where you just have to battle confounders. And in outcomes, benfotiamine is not shining - of course, maybe in combination with other stuff it might be of help.

1 Like
#1075

It’s mostly LDL. Per MR. Glucose dysregulation might play a role as well but it’s mostly LDL lowering.

2 Likes
#1076

@adssx and @CronosTempi I appreciate the ongoing dialogue + findings discussions, as I’m one of those fighting early-onset PD. My current simplifying protocol is diet (Mediterranean/pescetarian/minimal dairy + red meat) and exercise (resistance and 80%+ heart rate cardio).

I take B-12 and fish oil omega-3 supplements too, plus rapa (hence being here!). I guess I’ll be measuring any success at a decadal level of resolution.

#1077

Sorry to hear that. You might be interested in my “strategy”: Parkinson's disease - #429 by adssx

I changed a bit my “stack”. It’s now (besides the usual sleep, diet, exercise, stress management, etc.):

Unchanged:

  • Vaccinations (esp. shingles and tetanus)
  • Dapagliflozin 10 mg
  • Telmisartan 80 mg
  • Amlodipine 5 mg
  • Lithium orotate 1 mg

Added:

  • UDCA 2x500 mg: Good evidence + Ongoing RCT + Subjective benefits felt. I tried TUDCA, and it’s not as good as UDCA.

Testing:

Dropped:

  • Ezetimibe: My apoB is ~70 mg/dL, and cholesterol-lowering seems to be a net negative in PD. Choose your poison…
  • Selegiline: Lifespan extension not confirmed + potential negative cardiac effects
  • Theracurmin: Not enough evidence + no perceived subjective benefits
  • Terazosin: I gave it a try, some symptomatic benefits but I’m not convinced by the long-term cardiac
  • Tanganil: didn’t feel much, evidence weak
  • Semaglutide: felt worse on it, exenatide phase 3 failed

Undecisive:

Interesting:

#1078

If you take B12 take methylcobalamin.

Omega-3: There’s 0 evidence in PD. Actually, there’s 0 evidence in any condition, with the exception of EPA (eicosapentaenoic acid) in those with high triglycerides.