Chronic fatigue syndrome / ME insights through molecular biology


Chronic fatigue syndrome (CFS or ME) is a complex, long-term, and highly debilitating condition whose causes and mechanisms have been poorly understood until now.


The research of Professor Sonya Marshall-Gradisnik sheds new light on the pathological processes underlying ME/CFS – paving the way for future treatments.


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Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome – or ME/CFS –  is a complex, long-term, and highly debilitating condition. The causes and associated mechanisms of the condition have been poorly understood until now.


Professor Sonya Marshall-Gradisnik, Director at Griffith University’s National Centre for Neuroimmunology and Emerging Diseases, sheds new light on the pathological processes underlying ME/CFS – paving the way for future pharmacotherapeutic interventions.


In previous years, ME/CFS was commonly referred to as an illness hallmarked by debilitating fatigue that is not alleviated with rest. However, overwhelming chronic fatigue is just one symptom of many. A defining factor of ME/CFS is known as post-exertional neuroimmune exhaustion, which is the devastating escerbation of multisystemic symptoms experienced by individuals with ME/CFS. These symptoms vary in severity between patients, and can include impaired memory and concentration, wide-spread pain, neurosensory disturbances, orthostatic, or circulatory intolerances, sleep disturbances, immune dysfunction, gastrointestinal upsets, and temperature-intolerances, all of which significantly affect patients’ quality of life.


ME/CFS is thought to affect up to 24 million people worldwide, but the causes and pathology of the condition are difficult to pinpoint. There is still no routine diagnostic test, and diagnosis is based on the fulfilment of symptom criteria. Some symptoms can be treated or managed providing relief for some patients., hHowever, an effective treatment is lacking, and many ME/CFS patients report intolerance to many medications.


Aiming to change the landscape for ME/CFS is a team of researchers at Griffith University’s National Centre for Neuroimmunology and Emerging Diseases (NCNED), led by Professor Sonya Marshall-Gradisnik. Through their research, the NCNED team have revealed a wealth of new knowledge about the pathophysiology behind the condition, and the disordered physiological processes associated with ME/CFS. Their breakthrough findings provide hope of developing therapeutic interventions to treat and alleviate symptoms of ME/CFS.


Early groundbreaking research in the NCNED laboratory linked exposure to trauma or infection with the development of ME/CFS. For many years researchers have debated underlying mechanisms of the syndrome, leading some to speculate whether it has a psychological basis. This important study confirmed earlier research that ME/CFS is a biological condition, and not a psychological one.


Another A significant finding from the NCNED research team was the fact that ME/CFS is caused in part by the dysfunction of the transient receptor potential  – or “TRP”  family of ion channels.

Also known as ‘TRP threat receptors’, these channels come to the fore when the body is under any kind of threat, such as infection or trauma. This superfamily of ion channels garnered international recognition in 2021, when the Nobel prize in Physiology or Medicine was awarded to two researchers who discovered that these molecular transducers play an important physiological function. Found mostly on the plasma membrane or cell wall, they are involved in the perception of heat, cold, and mechanical stimulation and have enhanced our understanding of how the nervous system codes sensory information.


Dysfunctions of these ion channels, which allow the passage of ions across individual cells, are known as channelopathies and are implicated in many diseases. In a series of elegant studies, the NCNED team confirmed ME/CFS as a class of metabolic disorders known as TRP channelopathies. The team investigated the role of a specific transient receptor potential ion channel in immune cells in ME/CFS.


TRP ion channels have a vital role in calcium signalling in and out of cells, including in natural killer (NK) cells. NK cells are a type of white blood cell that play a key role in the immune system: to kill tumour cells or cells infected with viruses (target cells). Specifically, the NCNED researchers demonstrated that the calcium ion channel, Transient Receptor Potential Melastatin 3 (TRPM3), is impaired in ME/CFS.


As Marshall-Gradisnik describes, the science behind TRPM ion channels is complicated, ‘These are a group of 29 threat receptors comprising of seven sub-families. TRPM3 is one of at least eight variants of the TRPM ion channel, and likely has approximately 12 variants (or ‘isoforms’). Either genetic mutations found in the TRPM3 gene, coding for the TRPM3 ion channel, or changes to TRPM3 function through acquired factors, such as trauma or viral infection, are implicated in the development of ME/CFS.


Present in various organs and tissues including the pancreas, brain, kidney, and eyes, TRPM3 ion channels are a part of pain transmission and heat sensing pathways. Therefore, any dysfunction in such ion channels has widespread multi-system effects, which helps to explain the variety of symptoms presented in ME/CFS patients.


Marshall-Gradisnik explains, ‘ME/CFS patients have experienced marginalisation and disbelief with their illness in the face of profound disability and loss of activities of daily living. Validation of TRPM3 as the fundamental pathophysiology of ME/CFS paves the way for easier access to diagnostic tests as well as to a potential array of pharmaco-therapeutic interventions’.


The NCNED research team carried out delicate whole cell patch-clamp experiments to explore TRPM3 function in ME/CFS patients. Placing a tiny micropipette onto individual cells provided accurate measurements of the electrical properties, and function, of these cells. These experiments demonstrated that TRPM3 channel activity is impaired in ME/CFS patients. This channel activity impairment in NK cells affects the influx of calcium into the cell (that is, it disrupts its calcium regulation).


Apoptosis, or programmed cell death, is dependent on calcium regulation, so the ability of NK cells to cause programmed cell death is reduced in patients who have dysfunctional TRPM3 calcium ion channels.


ME/CFS patients report benefit and relief of symptoms using Naltrexone, but until recently there have been no studies demonstrating how Naltrexone alters the pathophysiological mechanisms of ME/CFS, the abnormal functional changes in the body that accompany chronic fatigue syndrome.


In 2019, Marshall-Gradisnik and colleagues published the first study confirming the potential utility of naltrexone hydrochloride  as a treatment for ME/CFS, and described the mechanisms of action. Promisingly, their research demonstrated that incubating NK cells from ME/CFS patients with naltrexone hydrochloride restored the function of TRPM3 ion channels, when the NK cells were stimulated with interleukin-2 (IL-2). IL-2 is a cytokine important in white blood cell signalling in the immune system. It aids NK cell interaction with target cells and improves cytotoxic abilities.


More recently, further NCNED studies confirmed the efficacy of naltrexone hydrochloride by demonstrating how it alters the pathophysiological mechanisms of ME. Opioid receptors present throughout the body are activated to regulate pain and inflammatory pathways. However, research shows that they also inhibit the function of TRPM3 and thus alter calcium concentrations, as well as affect NK cell functioning. Naltrexone hydrochloride is an antagonist of the opioid receptor and stops it from inhibiting TRPM3, therefore restoring TRPM3 activity, calcium concentrations, and normal NK cell function.


By clearly demonstrating the mechanism of action of naltrexone hydrochloride on restoration of TRPM3 activity in laboratory experiments, their study serves as a precursor and basis for the design of future clinical trials into the therapeutic benefits of naltrexone hydrochloride for ME/CFS.


The NCNED researchers have also showed for the first time that stimulation of NK cells with IL-2 significantly improves their cytotoxic abilities in patients with ME/CFS. Their studies reveal communication between TRMP3 signalling and IL-2 signalling pathways, which are important in immune regulation. Discovery of such crosstalk between these two pathways provides information into their functioning, and further understanding of the pathophysiology of ME/CFS.


The team developed a new immunofluorescence method to determine where TRPM3 and PIP2 reside within the cell. PIP2 is a membrane phospholipid molecule known to regulate several physiological functions including ion channel activity. Using one fluorescent dye to ‘tag’ TRPM3, and another to ‘tag’ PIP2 allowed the researchers to accurately visualise these two molecules under a microscope.


Excitingly, they found that TRPM3 and PIP2 are located very close to one another in NK cells.


‘Co-localisation’ like this suggests a strong functional connection between the molecules. PIP2 is a membrane phospholipid molecule known to regulate several physiological functions including ion channel activity.


Their study showed changes in TRPM3 and PIP2 co-localisation in ME/CFS patients compared to healthy subjects, suggesting that impaired TRPM3 function in the condition is related to PIP2 – which itself has a role in NK cell cytotoxicity. Importantly, the research further elucidates the intricacies of the impaired TRPM3 ion channel function pathology, and implicates PIP2 and IL-2 in this mechanism.


Finally, patients and researchers have an insight into the causes of this debilitating disease, which have remained elusive for so long. Such studies not only provide crucial information into the pathophysiological mechanisms, but also provide a foundation on which further mechanistic research can be conducted. This vital research paves the way for diagnostic tests and enables  pharmaco-therapeutic interventions to be explored, offering much needed relief for patients.


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