Notes - week of 2020/10/26

 Learned about PON1 and PD yesterday by attending web conference presentation by Beate Ritz:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922777/

Anthocyanins increase PON1 and are thought to protective against PD, but they also increase NO production - hmm ....

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Vitamin D levels are decreased in PD:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267215/

"After the discovery that the VDR and 1α-hydroxylase, the enzyme that converts vitamin D to its active form, were highly expressed in the substantia nigra, it was hypothesized that inadequate levels of circulating vitamin D may lead to dysfunction or cell death within the substantia nigra (25, 26)."

Active vit D (calcitriol) is mainly produced in the kidneys, as is klotho. a-syn is produced in the kidneys throughout lifespan. 

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Chronic kidney disease prevalence is lower in PD patients:

https://www.mdsabstracts.org/abstract/prevalence-of-chronic-kidney-disease-in-patients-with-idiopathic-parkinsons-disease-in-a-tertiary-care-hospital-in-mexico-city/

Interaction of a-syn with ENaC?

Larger epidemiological study from South Korea says that CKD is a risk factor for PD:

pubmed.ncbi.nlm.nih.gov/310...

There's another study from Europe that has the adjusted odds ratio for PD in CKD as 0.83 (95%CI 0.42–1.67):

pubmed.ncbi.nlm.nih.gov/330...

The Mexico City study findings, if true, are really interesting. It looks like the study  has not been published in a journal, so I will just give up on it for now.

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Is a-syn expression increased in PD not caused by SNCA duplication or triplication? 

https://pubmed.ncbi.nlm.nih.gov/22355802/

"A comprehensive study of multiple brain areas showed that membrane-associated monomeric α-synuclein levels were only modestly increased in the substantia nigra, and not in other brain regions, of PD patients compared to controls; even so, the levels in some PD cases were within the spectrum of control values. In contrast, in MSA, the membrane-associated α-synuclein increase was robust in vulnerable brain regions (Tong et al. 2010). It may of course be that neurons with the highest expression levels of α-synuclein are most vulnerable and succumb early in the disease process, giving their place to glia, thus confounding the results. To partly circumvent this issue, Gründemann et al. (2008) performed laser-capture microdissection studies, and reported a considerable increase of SNCA expression in surviving nigral neurons derived from PD brains compared with controls. However, this increase did not appear to be specific for SNCA (Gründemann et al. 2008). Therefore, the issue is still open."

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Of course I was not able to give up on the CKD and PD thing. I wrote about it on a forum: 

" There is an interesting study showing that a-syn is protective against kidney fibrosis:

nature.com/articles/s41467-...

a-syn interacts directly with the cell cytoskeleton, and apparently not via ENaC. However, since ENaC interacts bidirectionally with the cytoskeleton, then to me that means that a-syn can affect ENaC - which is very interesting and why the Mexico City study caught my attention in the first place. I suspect that susceptibility to PD and similar illnesses is related to differences in ion channel function/expression.

This brings up the question of whether a-syn production is generally increased in PD (it is, of course, in cases caused by SNCA duplication or triplication) and whether it increases along with progression. These seem reasonable questions to ask since sometimes if a protein becomes non-functional feedbacks are triggered that increase its production to try to make up for the loss of function."

and then I referred to the 2012 review quoted above. 

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Does this solve the MSA 'sodium paradox' - one would expect that the high salt diet that people with MSA use to mitigate orthostatic hypotension would cause increased neuroinflammation and increased rates of progression, but it an MSA mouse model found it doesn't - neuroinflammation increased a bit, but rate of progression was not increased by HSD. https://jneuroinflammation.biomedcentral.com/track/pdf/10.1186/s12974-020-1714-y.pdf

Human studies of HSD in multiple sclerosis, which like MSA is a demyelinating neurodegenerative disease, also did not find increased progression. 

Does HSD decrease a-syn expression from feedback from cytoskeletal changes (have to check and see if that actually happens)? If so, why are anti-fibrotic flavonoids (e.g., anthocyanins) associated with lower PD risk? They also increase expression of PON1. Is there a relationship between HSD and PON1?

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Acai extract increases erythropoietin production in mice by inducing 'hypoxic condition' in the kidneys:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071527/

might not be due to anthocyanin content:

"However, C3Glc [ cyanidine-3-glucoside ] alone did not alter the erythropoietin or Epo levels (Figure 2),"

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562914/ 

"PON-2 is located in the membrane of the mitochondria and in the endoplasmic reticulum. ... Among the three paraoxonase enzymes, PON-2 is the only one expressed in nervous tissues [69]."

"In vitro studies suggest that PON-2 can regulate the activity of epithelial sodium (Na⁺) channels [ ENaC ] by modulating its intracellular traffic and surface expression."

" Studies in mice have shown that both PON-2 concentration, mRNA expression and lactate activity of the enzyme are different between males and females. The high concentration of PON-2 in brain (in females, about three times higher than in males), protects neurons and astrocytes against oxidative stress toxicity and lipid peroxidation [77]."

"The enzymes PON-2 and PON-3 interact with mitochondria coenzyme Q10 [ CoQ10 ], leading to decreased oxidative stress [143,144]."

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Cetaceans lack PON1 activity: https://youtu.be/S36zqLDrecI?t=203

Do they have PON2 or PON3? Yes.

"A recent study by the Clark group identified a convergent functional loss of PON1 but not for PON2 or PON3 in marine mammals (79)."

https://www.jbc.org/content/early/2020/02/20/jbc.RA119.011789.full.pdf