“How is this topic related to gene-environment interactions?” — GEITPers such as George Leikauf might ask. 😉 Well, viruses, or viral infections are considered environmental signals, or stressors, to the patient or lab animal. Subsequently, after the viral infection, the phenotype (or disease) ME/CFS appears, and remains in the host for long periods of time — or forever. This disorder appears to be closely related to symptomatology that we see in Long-COVID disease.
One suspected causal protein (WASF3) has now been identified, which is apparently activated to elicit the clinical symptoms. Alternatively, WASF3 is downstream in the pathway (which includes activation of ER stress), and one or more other steps upstream still remain to be uncovered. 😊
WASF3 protein — that disrupts cells’ energy centers — might be a cause of chronic fatigue syndrome (CFS)
People living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) struggle not only with extreme exhaustion and the cognitive problems known as brain fog, but with a profound lack of information about what causes their symptoms and how to treat them. Scientists have yet to pin down the biology underlying the condition, which affects up to 2.5 million people in the United States alone, according to some estimates.
Now, researchers have identified a protein that’s present at unusually high levels in the muscles of people with ME/CFS and that disrupts cells’ ability to generate energy. The findings, reported today in the Proceedings of the National Academy of Sciences, could point to new therapeutics for this condition and for illnesses that share similar characteristics, such as Long COVID.
Akiko Iwasaki, an immunobiologist at Yale School of Medicine who was not involved in the work, praises the research as “very well done” but cautions that the suspect protein is likely “a piece of the puzzle, as opposed to explaining the whole disease.” The findings suggest it could act as one of several “middlemen” between whatever sparks the illness and symptoms such as fatigue, she says.
Paul Hwang, a physician-scientist at the National Heart, Lung, and Blood Institute (NHLBI), and his colleagues initially set out to study a 38-year-old woman with a cancer-promoting mutation in a gene called TP53. Unlike her brother and her father, who shared this mutation, the woman (referred to as S1 in the study) was experiencing extreme long-term fatigue, although she hadn’t received a formal ME/CFS diagnosis.
Hwang’s team examined tissue samples from her muscle, looking for abnormalities in biochemical pathways related to TP53. That search discovered high levels of a protein called WASF3 [encoded by the WASF3 gene, member of the WASP family-3 (Wiscott-Aldrich Syndrome protein group) on Chr 13q12.13]. WASF3 is known to play a role in a cell’s ability to migrate, Hwang says, but the team found a little-cited 2011 study of gene activity in ME/CFS patients that also had predicted it might contribute to that condition.
The NHLBI researchers wondered whether WASF3 was interacting with mitochondria, cellular compartments responsible for energy generation that have been suggested to malfunction in people with ME/CFS and Long COVID. Sure enough, by changing levels of WASF3 inside cultured cells from S1 as well as in other human and mouse cells, the team found the WASF3 protein could disrupt mitochondrial function. Specifically, high levels of WASF3 interfered with the assembly of mitochondrial proteins into molecular complexes that support normal energy production.
Hwang’s group next created genetically engineered mice to produce elevated amounts of WASF3. These animals also had defects in their mitochondrial function and were only able to run about half as far on a treadmill, compared with wild-type mice.
Curious as to whether these results might be relevant to people formally diagnosed with ME/CFS, the researchers compared muscle samples from 14 people living with the illness with those of 10 healthy individuals. They found higher average levels of WASF3—and lower levels of the associated mitochondrial protein complexes—in people with the condition.
“It’s extremely encouraging” to see this kind of detailed molecular approach applied to an understudied illness like ME/CFS, says Mady Hornig, a physician-scientist studying the condition at the Columbia University Mailman School of Public Health. Although the NHLBI researchers didn’t study Long COVID directly, their findings “stand to address a common set of health issues that are very tightly tied to disability in [both] Long COVID and ME/CFS,” she says.
Hornig (who personally has had Long COVID since 2020 adds that further work could try to address whether WASF3 also affects brain function. Deficits in brain energy metabolism may explain the cognitive fatigue that many ME/CFS patients find most debilitating, she says.
It’s not clear what causes high WASF3 levels in the first place. Hwang suggests a role for endoplasmic reticulum (ER) stress—a dysfunction of membranes that help the cell fold its proteins. Viruses can trigger ER stress, perhaps explaining why ME/CFS and related conditions often arise after infection. (S1 told Hwang her fatigue started after she had caught mononucleosis as a teenager.)
Several of the lab’s experiments support Hwang’s proposal: Both S1 and other people with ME/CFS had biochemical signatures of ER stress in their muscles, and treating S1’s cells in a dish with a drug that blocks ER stress—lowered WASF3 levels and restored mitochondrial function. On the flipside, using toxicants to artificially induce ER stress in cultured cells, or in mice, caused a rise in WASF3 levels, Hwang says.
But more work is needed to understand this link, says Pere Puigserver, a cell biologist at Harvard Medical School. ER stress can itself be prompted by mitochondrial dysfunction, making it hard to pin down the order of events leading to fatigue, he says. WASF3’s multiple cellular roles mean it might have other effects in people with ME/CFS, too, he adds.
Hwang acknowledges there are likely to be other pathways causing fatigue in ME/CFS and Long COVID, and that the drivers of illness might be different for different people. His group is now looking at drugs that could put the brakes on ER stress or decrease WASF3’s effects on mitochondria, with an eye toward designing a clinical study.
Excellent points, George. Clearly, you are a good candidate for “taking over” this email blog when I’m gone. 😉
I could have added (before sending the original email to all GEITP-ers) that:
[a] after a viral exposure (such as RSV or infectious mononucleosis), there is a huge gradient in response — from basically asymptomatic, to severe symptoms (due to underlying genetic differences);
[b] after the viral infection has been resolved, why does only a very small subset of patients develop chronic fatigue syndome (CFE), while almost everyone else does not develop CFE or myalgic encephalitis (ME)? It could be activation of WASF3, or a particular variant allele of the WASF3 gene, or (quite likely) one or more upstream genes in the network that ultimately lead to WASF3 activation.
[c] finally, can WASF3 be activated — without seeing the downstream effect of ER stress response?
This breakthrough study introduces far more questions than providing final answers. 😊
From: Leikauf, George
Sent: Tuesday, August 15, 2023 2:50 PM)
ME/CFS, long COVID-19 and even other forms of chronic fatigue are clearly related to gene-environment interactions by my definition. This is because — given the same environmental exposure — individuals always vary in their response. The variation in response is very likely to be due to genetic differences (as well as co-morbidities).
That said, we need to know reproducibity of this study and why family members with the same mutation lack the phenotype; this suggests modifier genes.
Lastly, since we now know that the phenotype “height” is associated with 2,500+ variant genes, I suggest caution about jumping in and saying “a gene is causative”, unless it has strong penetrance. This leaves me questioning whether any disease is a “single gene” disease.
Nonetheless, WASF3 might be a biomarker, if it shows sensitivity and specificity.
Thanks for calling attention to this protein.
George, the purist.