somatic mutation, neurodegeneration, organoids, eNOS, KLF2, LMNA, etc. (brief notes)

Stuff I wrote on YT comments in response to a question of mosaicism and aging:

"Interesting question, especially with respect to neurodegeneration (may partly explain the phenomenon of selective vulnerability as well as some sporadic cases of neurodegenerative diseases). There is a related article I would like to link to, but YT does not seem to allow that anymore. The article can be found by googling "Brain discovery explains a great mystery of Alzheimer's, Parkinson's" (February 15, 2019) about research conducted by Michael McConnell of UVA."

{ But I can link to it here (stupid YT) }

https://www.sciencedaily.com/releases/2019/02/190215135835.htm

Then found some YT videos on the topic ...

"This one is technical - https://youtu.be/y-XWoEjsg5Y  

The main takeaways for me were that there are distinct signatures for somatic mutations acquired during development and for those accrued during aging, and that chromothrypsis is sometimes involved. The presentation also referenced an interesting article on sex differences in gene expression in Alzheimer's (which is of course paywalled).  https://www.nature.com/articles/s41586-019-1195-2

Short and sweet - https://youtu.be/RIaE032cu_k Gives hope that we may be able to identify somatic mutations affecting the brain in living patients [using cell free DNA in cerebrospinal fluid]. Patient derived organoids hold a lot or promise for personalized medicine, but they won't work so well if the cause of illness is due to an unidentified somatic mutation."

~

I also watched a video presentation "Modeling Endothelial Dysfunction in LMNA-related Dilated Cardiomyopathy" by Nazish Sayed (2019) https://youtu.be/lhZZS6_-Cg4

and wish I could have taken notes because I've already forgotten a lot. The presenter discussed the use of organoid cultures for doing a 'clinical trial in a dish' and the results of experiments on co-cultures of endothelial cells and cardiomyocytes. The endothelial cells produced nitric oxide which in turn affected function of the cardiomyocytes.  KLF2, and inducer of eNOS expression as a target for drug therapy. Lovastatin is a KLF2 agonist and rescues endothelial dysfunction;  interesting example of a statin having effects not directly related to LDL.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557117/ 

"LMNA mutations that cause lipodystrophy or progeria show endothelial cell (EC)-dependent vascular dysfunction leading to premature atherosclerosis (–). Therefore, abnormalities in fibroblasts and ECs make it increasingly clear that dysfunction of non-myocytes in patients with cardiolaminopathy may contribute to progressive heart failure. Moreover, there is evidence to suggest that EC dysfunction can accelerate the progression of myopathy ().  ...

Lamins are expressed in all differentiated somatic cells and are considered important regulators of gene expression due to their interplay with signaling pathways, transcription, and chromatic organization (, ). Moreover, lamins can directly interact with transcription factors to regulate gene expression by interacting with transcriptional complexes. Indeed, our simultaneous profiling of chromatin accessibility and gene expression dynamics by combining ATAC-seq with RNA-seq showed downregulation of one such transcription factor, KLF2, in LMNA iPSC-ECs, and further knockdown studies validated the importance of KLF2 in LMNA-induced EC dysfunction. KLF2, a member of the Kruppel-like family, is regulated by biomechanical flow in ECs (, ) and in turn can regulate downstream genes such as eNOS, a gene primarily responsible for NO production (). An emerging function of nuclear lamins is to detect “outside-in” signaling such as shear stress, and to react by remodeling the cytoskeleton and extracellular matrix (). In other words, LMNA genes behave as a “mechanostat” to external forces, allowing the cells to adapt to the environment (). Knowing that by virtue of their location ECs are excellent mechanotransducers, we modeled EC dysfunction under physiological laminar flow. Our data showed that even under normal shear stress, LMNA iPSC-ECs exhibited EC dysfunction, which further validates our hypothesis that KLF2 is a key mediator for EC dysfunction in patients with LMNA mutation."

Such a great article! 

LMNA gene codes for several lamins including lamin A; LMNA mutations are associated with several diseases including Hutchinson Gilford Progeria syndrome.

 ~

Lovastatin also increases PON1 activity: https://pubmed.ncbi.nlm.nih.gov/20970413/

 It was found to be neuroprotective in MPP+ rat model (male rats) of Parkinson's; the effect was not mediated by an increase in PON2 activity.  https://pubmed.ncbi.nlm.nih.gov/25842176/

 

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