The extent of the ER stress problem

In my last video, I proposed endoplasmic reticulum stress (ER stress) as a possible cause for ME/CFS and long COVID. In that same video, I presented a list of other diagnoses that may be linked to ER stress. One of my next goals is mapping the total extent of the ER stress problem. My first conclusion: that list in my video was clearly too short.

There appears to be a whole family of diagnoses that are linked through ER stress. However, even a comprehensive review of ER stress in disease pathogenesis doesn’t come close to listing all of the associated diagnoses. So far, I have found

(From the above paper): Cancer, cardiovascular diseases (atherosclerosis, ischemia/reperfusion injury, myocardial infarction, heart failure), neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease), metabolic diseases (insulin resistance, type 2 diabetes, obesity), autoimmune diseases (rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease).

Additional autoimmune diseases are systemic lupus erythematosus and Sjögrens syndrome.

Another case of an overreacting immune system is mast cell activation syndrome (MCAS).

The pathogenesis of endometriosis also involves ER stress.

Then, there’s genetic diseases like Fabry disease, Ehlers-Danlos syndrome, cystic fibrosis and sickle cell anemia.

ER stress plays a role in a number of eye diseases like glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, uveal disease, ocular surface diseases and myopia.

Then there are problems which are commonly considered psychological, like autism and depression.

Additionally, ER stress is worsened by viral infections, some bacterial infections and aging. Microplastic, too, might exacerbate ER stress.

This is merely the starting point of my new research. There are likely many more genetic diseases that are related to ER stress. For example, there’s a group of genetic diseases that are termed endoplasmic reticulum storage diseases, including alpha-anti-trypsin-deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Are these linked to ER stress, too?

All in all, ER stress appears to be one of the major causes of disease, especially in the modern world. Common symptoms appear to be: fatigue, brain fog, inflammation and the consequences of cell death of the affected cell types. Some of these diagnoses may be risk factors for other diagnoses within this disease family. In some cases, we might be dealing with polygenic phenotypes that do not follow Mendelian inheritance patterns. Polygenic inheritance might even mean that the exact diagnosis within this disease family changes between a parent and a child (I would like to introduce the term “Fabriennian inheritance”). The link between Ehlers-Danlos syndrome and autism is already well established, but even this research paper doesn’t consider ER stress as a possible link.

Overall, the total scope of the ER stress problem would put it on one level with bacterial infections, viral infections and cancer. Still, there is no coordinated research. In the case of Fabry disease, the problems arising from ER stress are not taking seriously, despite being definitely proven. That’s why it’s important to raise awareness for this problem.