The researchers also speculated – and this is where things get really interesting – that the results could help explain certain issues with LRRK2-associated Parkinson’s such as penetrance and progression. By this they mean that tissue levels of AdoCbl could possibly help explain why some individuals carrying the LRRK2-G2019S variant do not go on to develop Parkinson’s, and differences in tissue levels of AdoCbl could also help to explain the differences in speed of Parkinson’s progression across different people with LRRK2-associated PD.
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' Genetically, mutations of the leucine-rich repeat kinase 2 (LRRK2) gene associated with sleep disorders and PD were significantly decreased when melatonin was administered (Sun et al., 2016) '
People with PD have reduced B12 levels which can allow homocysteine levels to increase and that isn't good for anyone. People with PD have elevated levels of homocysteine and this is associated with development and progression of PD. It can also contribute to peripheral neuropathy(PN) which PwP have at a rate higher than in healthy controls. Elevated homocysteine levels are also associated with increased anxiety, depression and cardiovascular disease(CVD), which again appear to be at higher levels in people with PD than healthy controls.
On the plus side, melatonin counts as two of its multitude of anti-PD effects, the ability to reduce homocysteine levels as well as the neurotoxicity of homocysteine. Also on that list is its abilities to work against CVD, PN, anxiety and depression.
Unfortunately, melatonin levels decline with age and even more so in PwP.
Please note that post mortem, it has been observed that LRRK2 was unregulated in PWP without the LRRK2 gene mutation. I do not have the scientific knowledge to understand that but down regulating LRRK2 can benefit all PWP is my takeaway.
Can someone with a science background explain this? And how is LRRK2 both a gene and a protein?
Unfortunately, taking adenosylcobalamin doesn't ensure a high level of it in the body.
From The Science of Parkinson's; "All forms of vitamin B12 are absorbed with similar efficiency in the blood stream, and they are reduced to the core cobalamin molecule once inside the cell, and it can then be converted into AdoCbl – regardless of the form of B12ingested." ncbi.nlm.nih.gov/pmc/articl...
The study I linked to, explains that all forms of ingested B12 are reduced to "plain" cobalamin. It's then the job of the mitochondria to produce adenosylcobalamin from the cobalamin.
AdoCbl is one of the most prevalent form of B12in our body’s cells. In the mitochondria (the power stations of cells), AdoCbl plays an important role. A deficiency of AdoCbl leads to the impairment of ATP production (the same ATP we discussed above) and, as a result, this leads to chronic fatigue and exhaustion, etc.
(NOTE he is specifying that it’s AdoCbl that plays an important role in mitochondria.)
So AdoCbl is one of the two enzymatically active forms of vitamin B12 and this new research suggests that it can modulate the hyperactive form of the LRRK2 protein?Exactly.The researchers found that of the 4 forms of vitamin B12, only AdoCbl exhibited an ability to inhibit the hyperactive LRRK2-G2019S protein.
(NOTE: The researchers established that ONLY AdoCbl exhibited an ability to inhibit hyperactive LRRK2-G2019S protein. Distinction to note, it’s LRRK2-G2019S not LRRK2. Regarding LRRK2,
Interestingly, the investigators found that AdoCbl caused conformational changes to the LRRK2 protein and disrupted thedimerization of LRRK2 proteins.What does ‘dimerization’ mean?LRRK2 proteins can only function when they bind to other LRRK2 proteins (Click here and here to read more about this). This binding together is called dimerizing (or dimerization).The dimerization of LRRK2. Source: ResearchgateAnd AdoCbl blocks the dimerization of LRRK2? So LRRK2 can’t function?It is certainly reducing the levels of LRRK2 activity (as good as many of the LRRK2 inhibitors that are being developed).
NOTE: AdoCbl and only AdoCbl causes the LRRK2 to not bind to other LRRK2 (dimerization) so, AdoCbl is the form of B12 that I need.
AdoCbl was causing the proteolysis of LRRK2 – that is the breaking down of the protein. This is something the other LRRK2 inhibitors do not do.
NOTE: AdoCbl was causing LRRK2 to break down. That is good! But, it is only in worms so whether any of this will translate to humans is unknown.
Next, the investigators looked at what happens to LRRK2 activity levels in an animal model of Parkinson’s – specifically, a model that involves a pesticide toxin (called Rotenone – Click here to read a previous SoPD post on pesticides). When they looked at dopamine neurons in animals treated with rotenone, the researchers observed a 10-fold increase in certain markers of LRRK2 activity. They also reported disruption of cellular waste disposal (or autophagy) markers caused by rotenone treatment.
NOTE: ROTENONE, ROUNDUP (in animals) causes a 10-fold increase in LRRK2 activity. And disrupted autophagy.
test, the researchers caused oxidative stress on cells and observed an increase in LRRK2 activity, which could be reduced by treatment with anti-oxidants.
NOTE: oxidative stress causes an increase in LRRK2 activity.
Thanks for that. Of course you're correct that mitochondria require adenosylcobalamin. And I understand that it's the only form of B12 that's been found to inhibit the hyperactive LRRK protein.
The problem is, you can't just take oral adenosylcobalamin and assume the levels in the brain (or elsewhere) will elevate; adenosylcobalamin, methylcobalamin and hydroxycobalamin are all turned into cobalamin after ingestion. Then it's up to the mitochondria to produce the adenosylcobalamin that can actually be used to inhibit LRRK-G2019S.
So my point was just that it doesn't matter what form of B12 one takes. What matters is whether or not one's mitochondria can turn cobalamin into adenosylcobalamin in enough quantities to make a difference in Parkinson's symptoms.
although it’s just a worm study, it clearly states that adenosylcobalamin is the type of B12 needed for the LRRK2 suppressant effect. I quoted SOP saying just that. Whether or not one’s mitochondria can convert enough to make a difference is unknown as it was a worm study. But that does not mean that the point clearly stated in SOP and pasted above is not valid. In the study being referenced, it is specifically adenosylcobalamin.
' Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria. '
I think there may be a reason or two why melatonin is made in every cell in the body and its receptors are found throughout the body. It's that age related decline and additional decline in PwP that may not be so helpful.
There aren't studies that I have seen to support that often mentioned contention. I do not cycle melatonin other than upward over years since it has been declining for many many years.
Do you know what studies say regarding how to increase melatonin production? I’ve read that am light exposure and vitamin D in the am can increase melatonin later, based on circadian cycle. I don’t know if that’s correct though, just read it somewhere.
Do you have a preferred melatonin form or company?
I wrote something about that that I will link you to. One way that many people can use when it is too cold outside to get that morning and late afternoon sun light exposure is red light therapy. I have been wondering if increased melatonin production is one of the main benefits of red light therapy???
What do you use for redlighht therapy> I have a sauna with infared lights. Will that work? How long should I stay in? What temperature and how often? Thank you!
Thanks for the link. I'm fascinated by melatonin, especially it's relationship to infrared light. Here's my most recent favorite paper; ncbi.nlm.nih.gov/pmc/articl...
Thank you for the link, I had not seen that before. I'm glad they decided to talk more about melatonin from a perspective other than pineal gland production, given that the gut contains 400 times the amount of the pineal gland and if melatonin is produced in every mitochondria in the body, that again dwarfs the amount in the gut.
The effects of the combination of short chain fatty acids and melatonin in the gut are only more recently being discussed but it seems fairly clear that they work together in synergy to help maintain gut homeostasis at a bare minimum. My take is that they feed off of each other in a type of pro health cycle that is the opposite of how oxidative stress and inflammation work in synergy as an anti health cycle to promote disease and degeneration. Every PwP should benefit from improved gut homeostasis as preliminary FMT studies have suggested so far.
Given the well proven safety of melatonin in hundreds of human studies even at high dosing, I sure would like to see a 150 mg+ /day study in PwP. So far there is one 10 mg/day study and two 50 mg/day studies in PwP which both produced positive results in the participants. We know so much more about melatonin than just 10 years ago, but I feel in the big picture it is just the tip of the iceberg and this is not just regarding humans, but animals and plant life on the planet too. When they apply melatonin to seedlings it acts to improve the resulting plant very significantly.
I would hope high dose melatonin studies are just around the corner, considering how available and safe it is. I think photobiomodulation may actually hold more promise though, and there are quite a few studies taking place utilizing it.
Researchers often comment on Mother Nature's brilliance in having mitochondria produce melatonin, since mitochondria are a major source of oxidative stress; large amounts of reactive oxygen species are produced right where melatonin is highest, so they can be scavenged immediately. Not sure if melatonin circulating in the blood can have as profound an impact as that produced intracellularly.
Infrared light has the ability to prompt mitochondria to produce melatonin, and since that melatonin doesn't circulate, it's probably not as likely to cause somnolence. Those who get very little sunlight may benefit the most from photobiomodulation. Modern indoor lighting has virtually no infrared, and "low-e" windows are designed to filter it out.
Morning exercise has also been shown to elevate melatonin levels, both immediately and as a result of increased pineal production at night. So in my uneducated opinion, exercising outdoors in the early am has the potential to be doubly neuroprotective. Now if I could only get myself to do it!
Winter weather in most areas make such an exercise routine almost impossible, but the other seasons are doable.
A powerful enough IR wrap around the abdomen seems like it might be quite useful to help restore the gut microbiome to a more optimal balance, as well as induce healthier responsiveness in some of the major organs, which should be helpful for the health of the body as a whole.
Sorry, I wasn't trying to argue with the premise of the SoP article, only trying to point out that people are different from worms and animals and that using adenosylcobalamin in humans isn't as straightforward.
I definitely think taking B12 is a good idea. Hopefully, raising overall levels will lead to higher adenosylcobalamin levels and have the desired effect on the LRRK protein.
Because adenosylcobalamin is the form that specifically down regulated LRRK2 (in worms) and it is as safe as the other forms and accessible, I am switching my B12 to adenosylcobalamin.
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