cancer vs. neurodegeneration round 3: LRRK2 and B12, covid - brief notes

Mutations in the gene that codes for LRRK2, a kinase, are a risk factor for Parkinson's disease. Increase in the kinase activity of LRRK2 caused by these mutations leads to increased apoptosis and neuronal loss in PD.  

Vitamin B12 inhibits LRRK2 kinase activity:

https://pubmed.ncbi.nlm.nih.gov/21198553/ 

"Herein we identify 5'-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity. Multiple assays show that AdoCbl directly binds LRRK2, leading to the alterations of protein conformation and ATP binding in LRRK2. ...

Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the future. "

 

High B12 status has been found to be associated with increased  risk of lung cancer:

"Circulating concentrations of vitamin B12, based on pre-diagnostic blood samples from the LC3 consortium on over 5,000 case-control pairs, were positively associated with lung cancer risk, and in contrast to the VITAL study, this association was consistently seen across sexes, former and current smokers, time from blood draw, and geographic region (eFigure 1). Confirming these results, the MR analysis based on genetic data indicated that higher concentrations of vitamin B12 increased the risk of lung cancer, especially for adenocarcinoma and small-cell carcinoma, with no association seen for squamous cell carcinoma."


Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis:

https://www.nature.com/articles/s41598-021-81639-0

 "Pathogenic links between cancer and Parkinson’s disease (PD) are emerging: while cancer cells can proliferate indefinitely, diseased neurons die prematurely, placing cancer and neurodegenerative disease at opposite ends of a spectrum of aberrant cell survival4. Overactive LRRK2 is a common genetic cause of PD5, which when inhibited or knocked out perturbs pulmonary surfactant homeostasis in alveolar type II (AT2) cells6—a main cell of origin in LUAD7 [lung adenocarcinoma].  ...

In summary, marked LRRK2 reduction was associated with tumors predicted to have altered distal lung architecture, dysfunctional surfactant metabolism, hyperproliferation and potentially altered innate tumor immunity—in patients who continued to smoke and ultimately suffered worse survival."

Interesting that the tumor-promoting effect of loss of LRRK2 is attributable to changes in surfactant metabolism and immunosuppression, rather than being directly tied to reduction in apoptosis. 

Also interesting  that alveolar type II pneumocytes (AT2) are the same type that become infected in covid-19. There is a study from Turkey that found high B12 status associated with poor outcomes in covid-19 - somewhat surprising given that the elderly are often B12 deficient.

https://pubmed.ncbi.nlm.nih.gov/33555131/

The article discusses the possibility of reverse causation relating to comorbidities. Liver injury can result in elevated serum B12 levels due to reduced hepatic storage resulting from either excess release or reduced clearance:

https://pubmed.ncbi.nlm.nih.gov/28331419/ 

[edit/update 2022-05-04] Vitamin B12 can exist as potentially harmful, inactive analogues and apparently these are hard to distinguish from functional B12 in tests. Alzheimer's patients were found to have higher analogue/functional B12 ratio  https://pubmed.ncbi.nlm.nih.gov/11173886/ . Perhaps higher B12 status in severe covid patients was reflective of higher B12 analogue levels.

Another consideration is that  B12 status may serve as a marker of animal protein intake and may therefore correlate with baseline mTOR activation, which may affect covid-19 severity. 

However, it seems the potential for a causal chain linking B12, LRRK2 inhibition, and AT2 function should be investigated in the context of covid-19, as well as that of lung adenocarcinoma.

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