The structure of the BDNF protein

The structure of the BDNF protein

Principal Investigators

Prof Jo Nijs & Prof Lode Godderis

Institutions

Vrije Universiteit Brussel, University Hospital Brussels & University of Leuven

Funding

ME Research UK

Background and aim

Chronic pain is debilitating and very common, and is a particular problem in people with ME/CFS, 80–90% of whom report severe pain and/or muscle or joint pain. In the past decade, a number of studies, including those funded by ME Research UK (see study), have increased our understanding of pain in the illness. Overall, there is now evidence that brain-orchestrated inhibition of pain at rest and during exercise is impaired in people with ME/CFS, in line with the occurrence of hypersensitivity of the central nervous system (central sensitization). The logical next step is to unravel the mechanisms of the pain associated with central sensitivity by examining factors known to increase it. One such factor is brain-derived neurotrophic factor (BDNF), a protein produced by a variety of cells, including sensory neurons, motor neurons, immune cells such as leukocytes, microglia, and astrocytes. In general, BDNF serves as a key regulator of synaptic plasticity in the peripheral and central nervous system (i.e. spinal cord and brain regions like the hippocampus and cortex), and it increases the sensitivity of the pain pathways in the central nervous system.

Genetics is concerned with changes to sequences of DNA (the genotype) which are then inherited. However, a relatively new discipline, epigenetics, has revealed that changes in gene expression (the way information from a gene is used to make products, usually proteins) can be affected by other factors and processes, including childhood development, drugs, diet, environmental chemicals, and even the aging process itself. In particular, epigenetic modifications (through, for example, DNA methylation) can have effects on the function of genes over the long term, and may be involved in a range of illnesses, such as diabetes or cancer (See a diagram). Epigenetic research is in its infancy in ME/CFS, but one recent analysis of epigenetic modifications of DNA (read more) found evidence that immune cell regulation differs between ME/CFS patients and controls, a result that accords with what we already know about functional changes in immune profiles in the illness.

Applying an epigenetic perspective to the understanding of pain in ME/CFS may provide important insights and lead to new strategies to treat pain. Accordingly, a cross-disciplinary team of researchers at the University of Leuven, Vrije Universiteit Brussel, and University Hospital Brussels have designed an exploratory study to investigate the presence of epigenetic changes in promoter I and promoter IV of the BDNF gene and whether these are more prevalent in ME/CFS patients than in the general population. Given the current understanding of BDNF’s role in central sensitization, their hypothesis is that epigenetic activation of the BDNF gene is related to the pain experienced by people with the illness. All study participants will undergo blood sampling for epigenetic analysis, and complete outcome measures for the quantification of pain inhibition and facilitation, and assessment of real time physical activity and symptoms. In addition, differences in epigenetic methylation pattern and stability over time will be related to changes in pain and symptom fluctuations. For the investigation, participants will attend the university hospital for two consecutive times in four days, allowing the study of the temporal stability of the epigenetic measurements and to examine possible associations between epigenetic changes and symptom fluctuations as well as pain inhibition and facilitation.

Further reading

Brain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: a new therapeutic target? Expert Opin Ther Targets, 2014. Read more.
A Scientific Illustration of How Epigenetic Mechanisms Can Affect Health. National Institutes of Health, USA. Read more.
The emerging role of epigenetics in cardiovascular disease. Review in Therapeutic Advances in Chronic Disease, July 2014. Read more. Next-generation sequencing and epigenomics research: a hammer in rearch of nails. Review in Genomics Informatics, March 2014. Read more.