Wednesday, April 24, 2024

6208 - Alzheimer’s, Parkinson’s, and Lewy body dementia

Make it BIG!

DNA damage secondary to radiation, chemical agents, or accumulation of reactive oxygen species (ROS) is the main cause of cellular senescence-inducing stress. Proliferation-induced telomere shortening can also activate the DNA damage response, which in turn leads to activation of the p53–p21 pathway, inhibition of cyclin-dependent kinase (CDK)–cyclin complexes, and formation of the DREAM complex, which represses cell-cycle genes, leading to cell-cycle arrest and senescence. 

Activated p21 can also induce further ROS production, forming a vicious circle. In addition, impaired mitophagy can lead to mitochondrial dysfunction and excessive ROS production. ROS can induce senescence independently of the DNA damage response by activating the p16–RB pathway via activation of ERK, which inhibits BMI1 and thereby enables activation of p16, and by activating p38MAPK signaling, which upregulates ETS2 and in turn activates p16, and by inhibiting NAD+, which leads to reduced expression of sirtuin 1 and activation of FOXO3, which activates p53. 

P16 inhibits the formation of CDK4/6–cyclin D complexes and thereby promotes formation of the RB–2F complex, which inhibits the transcription of cell-cycle genes. Oncogene activation can activate the p53–p21 pathway not only via the DNA damage response, but also via the ARF–MDM2 signaling. In addition, oncogene activation can activate the p16–RB pathway via p38MAPK signaling. Loss of tumor suppressor genes induces senescence via Akt–mTOR signaling, which activates p53. 

Other factors that regulate the p53–p21 pathway include α-Klotho, MBP1 and p300. Epigenetic alterations such as methylation (Me) and acetylation (Ac) can induce senescence through the p16–RB pathway. NF-κB signaling regulates the senescence-associated secretory phenotype (SASP) and together with the transcription factor C/EBPβ, co-activates promoters of SASP genes, such as those that encode pro-inflammatory cytokines. 

The DNA damage response protein ATM together with NEMO activates the NF-κB–C/EBPβ signaling pathway. ROS can activate the SASP not only by promoting nuclear translocation of NEMO and activation of ATM, but also by inhibiting sirtuin 1 and activating p38MAPK and TGFβ, which in turn activate NF-κB. Heat shock, metabolic disorders, mechanical damage, and endoplasmic reticulum (ER) stress can also activate the NF-κB–C/EBPβ pathway via p38MAPK signaling. 

Cytoplasmic DNA accumulation can trigger aberrant activation of cGAS-STING cytoplasmic DNA sensors and promote the SASP via activation of NF-κB. Impairment of autophagy hampers degradation of the transcription factor GATA4, which activates NF-κB and leads to initiation of the SASP. Notably, oncogenic Ras can activate C/EBPβ via ERK–p90 signaling and histone epigenetic changes can regulate the SASP independently of the NF-κB–C/EBPβ pathway. 

ARF, ADP-ribosylation factor; BMI1, B lymphoma Mo-MLV insertion region 1 homolog; cGAS, cyclic GMP–AMP synthase; CHK, checkpoint kinase; ERK, extracellular regulated protein kinases; ETS2, E26 transformation-specific proto-oncogene 2; E2F, early 2 factor; FOXO3, forkhead box protein O3; IKK, IκB kinase; MDM, mouse double minute 2; MSK, mitogen- and stress-activated protein kinase; NEMO, NF-κB essential modulator; STING, stimulator of interferon genes.

I highlighted the words that I thought needed more explanation.

Why did I post this? I liked the picture. 


Elephant's Child said...

How I hope that cures can be found. Yesterday.

Bilbo said...

I think the Readers' Digest version of this is: "Getting old sucks for a lot of reasons."

Cop Car said...

There will be a test tomorrow.

Margaret (Peggy or Peg too) said...

Please no pop quiz!

Anonymous said...

I didnt even understand some words. Let alone the acronyms. Suggest you link the technical words and acronyms to Wikipedia Mike.

Mike said...

Sue - I think they are finally making some headway. I don't know if it will be in time for us or not.

Bill - It's that damn reactive oxygen species (ROS)!

CC - Spelling will be critical.

Peg - Hey, you have 24 hours notice!

Anon - I thought I got most of the strange words linked to Wikipedia. said...

And this IS the English version, am I right? Oy vey.


Kirk said...

Yes, that picture is aesthetically pleasing.

By the way, I managed to spell "aesthetically" without getting spellchecked! Perhaps a sign that my own dementia is still a ways away.

Lady M said...

Hee hee- if I don't understand much of this, does it mean I am on the fast track to dementia.

Mike said...

Robyn - I'm not really sure. 😁

Kirk - I'm impressed. Spell check would have raked me over the coals on that one.

Lady - There will be a test soon and we'll find out.