Yes. Risk avoidance happens in people at a prodromal stage, before official PD diagnosis. So if they are avoiding surgery it might select for those who have the surgery to be more non-PD people, making it seem like surgery is protective. Reverse causation. Meanwhile PD patients on dopa drugs escalate risk taking, gambling etc. - so if we could find stats that show PD people on dopa drugs having more plastic surgery than PD people not on those drugs, we might establish if this hypothesis has evidence for it.
They’re definitely higher income / net worth than average which correlates positively with intelligence so it’s all tangled up.
I moved the above posts here as they were unrelated to hypoxia.
α-Syn mutations activate ACLY, which enhances cytoplasmic p300 activity
Cytoplasmic p300 hyperactivation stimulates mTORC1 to inhibit autophagy
ACLY inhibition restores autophagy and reduces α-Syn aggregates in neuronal models
ACLY inhibitors rescue pathology in both zebrafish and mouse α-synucleinopathy models
Triplications and certain point mutations in the SNCA gene, encoding alpha-synuclein (α-Syn), cause Parkinson’s disease (PD). Here, we demonstrate that the PD-causing A53T α-Syn mutation and elevated α-Syn expression perturb acetyl-coenzyme A (CoA) and p300 biology in human neurons and in the CNS of zebrafish and mice. This dysregulation is mediated by activation of ATP-citrate lyase (ACLY), a key enzyme that generates acetyl-CoA in the cytoplasm, via two mechanisms. First, ACLY activity increases acetyl-CoA levels, which activate p300. Second, ACLY activation increases LKB1 acetylation, which inhibits AMPK, leading to increased cytoplasmic and decreased nuclear p300. This lowers histone acetylation and increases acetylation of cytoplasmic p300 substrates, like raptor, which causes mechanistic target of rapamycin complex 1 (mTORC1) hyperactivation, thereby impairing autophagy. ACLY inhibitors rescue pathological phenotypes in PD neurons, organoids, zebrafish, and mouse models, suggesting that this pathway is a core feature of α-Syn toxicity and that ACLY may be a suitable therapeutic target.
PD is strongly linked to epigenetic dysregulation, particularly in alterations of histone modification. Previous studies have reported an alteration in the acetylation of histone H3, which correlated with both Lewy body stage and substantia nigra pigmentation scores.47,48 In addition, genome-wide analyses showed dysregulation of H3K27 acetylation in the prefrontal cortex of PD brains.49 Another study showed H3K4me3 was increased in PD bulk substantia nigra.50 Pathogenic A53T α-Syn inhibits H3 acetylation by binding directly to histones11 or through interaction with the transcriptional adapter 2-alpha (TADA2a).22 Despite the growing evidence for the significance of epigenetic changes in PD brains, the mechanisms by which these changes occur and how they induce pathological phenotypes remain unclear. Our data suggest that such alterations may, in part, be due to decreased nuclear p300 levels/activities.
Our data suggest that since A53T α-Syn causes ACLY activation, which hyperactivates mTORC1 and causes autophagy inhibition, there is the potential for a positive feedback loop, as α-Syn is itself an autophagy substrate that will accumulate further after autophagy is compromised. It is likely that other pathways, like proteasomal degradation, can buffer the deleterious effects of autophagy defects in A53T α-Syn-expressing cells or cells with SNCA triplication. However, if such buffering pathways, or autophagy itself, are further compromised, then such a feedback loop could be unleashed. We speculate that one of the reasons why many neurodegenerative diseases only manifest in later age is because such feedback processes are kept in check for decades until additional processes like aging, which compromise brain autophagy,51 overwhelm the homeostatic balances.
What do you think @John_Hemming?
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What this seems to say is that there is a cycle which is sensible really.
PD is strongly linked to epigenetic dysregulation , particularly in alterations of histone modification.
So that is my hypothesis.
The real issue for acetylation is the availability of the substrate to create acetyl-CoA which is our good friend 2-hydroxy-1,2,3-propanetricarboxylate. * C6H5O7-3
Something coming down the pipeline. @adssx
It’s quite interesting to me, I’d give it a go 
A ASHA-091 is designed to specifically inhibit DRP1 activation, a regulatory protein with a role in the fragmentation of mitochondria.
“A key feature of most neurodegenerative disease … is the hyper-fragmentation of mitochondria. This promotes neuroinflammation, neuronal dysfunction, and ultimately neurodegeneration,” the company reports on a therapy webpage. ASHA-091 is a “first-in-class highly specific inhibitor of mitochondrial fragmentation that restores normal cellular function.”
This is a fun story about a woman that can smell parkinson’s. Her ability was turned into a test that predicts the disease much earlier than has been done before:
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Given that Parkinson’s is most likely caused by long term exposure to industrial toxins (eg herbicides and insecticides) taking supplements that boost Glutathione and other detoxification pathways might be a good way to stop progression of Parkinson. This is supported indirectly by Parkinson onset being preceded by 10 years or more of reduced Glutathione levels. Gluthathione levels decrease with age.
Grey hair is the most visible symptom of Glutathione depletion in old age, and results from accumulation of hydrogen peroxide in the blood, which bleaches hair follicles.
Supplementing directly with glutathione does not work well, since it is broken down by digestion, so works no better than supplementing with NAC (a source of cysteine, the critical amino acid used for glutathione synthesis in the body). However, the enzymes required for glutathione synthesis decreases with age, so relying on NAC supplements requires increasing the dosage as you age and eventually requires very high doses of up to 9 g/day, which has the drawback of producing high levels of toxic Hydrogen Sulfide in the gut, which might not be a good idea with Parkinson’s since toxins that cause Parkinson’s are believed to travel from the gut to the brain via the Vagus nerve (bypassing the BBB).
Using IV glutathione doesn’t work either, since the glutathione just circulates in the blood and cannot be absorbed by neurons in the brain (though liver cells are able to absorb some glutathione from the blood).
Two alternate ways to raise Glutathione in the brain that avoid the toxic side effects of NAC:
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Intranasal Glutathione, which may be able to bypass the BBB, though the experimental results so far are disappointing : https://www.michaeljfox.org/news/ask-md-glutathione-and-parkinsons, possibly because neurons, like most cells, have trouble absorbing Glutathione.
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Oral supplementation with Gamma-Glutamyl-Cysteine, a precursor that does NOT break down in the gut and is easily absorbed by all cells (and converted to Glutathione inside cells without depending on the enzyme that decreases with old age). Unfortunately the only source is the commercial product Glyteine from Continual-G which costs $1.5 per 400mg dose and you need at least 2 doses per day. I use 4 doses per day, since each dose is only effective for around 3-4 hours : I don’t have Parkinson’s but I do have constant brain fog and trouble with memory unless I use this supplement…
There may be additional detoxification pathways that may need to be strengthened, using supplements like Milk Thistle or Green Tea extract , but the evidence for benefits for Parkinson’s so far is not good.
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Interesting. I don’t know if glutathione depletion is the mechanism, but there does appear to be some potential association with gray hair.
Preclinical signs of Parkinson’s disease: A possible association of Parkinson’s disease with skin and hair features
https://www.sciencedirect.com/science/article/abs/pii/S0306987719301707
“We hypothesize that earlier age at onset of hair greying, greater tendency to sunburn, difficulty tanning and dysregulation of sebum production are more common among PD patients due to genetically determined lower constitutive amounts of melaninand accumulation of α-synuclein in the skin, which leads to disrupted synthesis of peripheral melaninand dysregulated sebum secretion.”