ReviewEpigenetics and migraine; complex mitochondrial interactions contributing to disease susceptibility
Introduction
Migraine is a common neurological disorder characterised by severe head pain and an assortment of additional symptoms which can include nausea, photophobia, phonophobia and for some subtypes of migraine additional neurological symptoms. Migraine is classified according to the International Headache Society into two broad categories namely migraine without aura (MO) and migraine with aura (MA) (Eriksen et al., 2004, Olesen and Lipton, 1994). Most patients suffer from MO, with only 20% of sufferers experiencing an aura before the onset of a migraine attack. Approximately 12% of the Caucasian population suffers from this debilitating disease with almost 2/3 of sufferers being female. Migraine is classified by the World Health Organisation (WHO) as one of the top twenty most debilitating diseases in the developed world and poses a significant personal and economic burden (Leonardi et al., 2005).
In 2010 it was estimated that headache disorders in Europe cost an estimated €43.5 billion per year (Gustavsson et al., 2011). It has been shown that the cost incurred by continuous absenteeism from the work place as a result of employees being unable to work due to debilitating migraine attacks is actually higher than the direct cost of treatment. Also the total percentage of costs attributed to loss of work place productivity caused by chronic disease is by far dominated by migraine with 89% attributed to migraine and only 19% for other chronic conditions (Schultz et al., 2009). Current therapies are only effective for a proportion of sufferers and new therapeutic targets are desperately needed to alleviate this burden.
Various theories explaining the pathophysiology of migraine have been tested and modified for the last eight decades. The most supported current view is that migraine is a complex multifactorial disease with both predisposing genetic variance and environmental factors contributing to the final phenotype. The actual biological mechanism involved in a migraine attack is still debated, but is thought to be caused by activation of the trigeminal nerve causing pain sensation in the sensor cortex of the brain and/or a dysfunction of the neuronal nuclei located within the brain stem (Ho et al., 2010). The trigeminal vascular theory states that activation of the trigeminal nerve system by a neural, vascular or neurovascular trigger leads to a migraine. The trigeminal nerves carry pain signals from the meninges and blood vessels infusing the meninges to the trigeminal nucleus in the brain stem which in turn sends signals to the sensor cortex via the thalamus. The sensor cortex processes pain signals and other senses, thus leading to the sensation of pain experienced during migraine attacks (Oshinsky and Luo, 2006). This mechanism is illustrated in Fig. 1 below.
Dysfunction of neuronal nuclei can be explained by migraine pain and trigeminovascular activation being caused by a central mechanism which may not require a primary sensory input (Goadsby and Akerman, 2012, Lambert et al., 2011). The most recent theory explaining migraine pathogenesis describes migraine as a dysfunction of the subcortical brain structures including the brainstem and diencephalic nuclei which are involved in modulating sensory inputs. The theory suggests that aura is triggered by dysfunction of these nuclei and that the same mechanism is responsible for the pain and other symptoms experienced during migraine attacks (Akerman et al., 2011). This theory challenges the importance of cortical spreading depression (CSD) in generating a migraine attack, a process which has previously been emphasized. CSD is a wave of neuronal and glial depolarization/neuronal hyperexcitability followed by a long lasting suppression of neural activity (de Almeida et al., 2009). This electrophysiological event has been linked to aura in the human visual cortex and is thought to be partly responsible for the sensory and motor disturbances experienced during MA attacks.
Section snippets
Heritability and migraine: a significant genetic contribution
Heritability is the proportion of a trait or disease phenotype which can be attributed to genetic variation. The official definition of heritability is the “proportion of phenotypic variation (VP) that is due to variation in genetic values (VG).” Genetic values (VG) include the combined effect of all loci as well as interactions within (dominance) and between (epistasis) loci. Two different basic heritability values can be calculated namely broad-sense and narrow-sense heritability. Broad-sense
Epigenetics
Epigenetics refers to partially heritable alterations which influence gene expression, not due to changes in DNA sequence but rather as a result of higher structural modifications. There are three main systems involved in epigenetic structuring namely; methylation, histone modification and RNA-associated silencing (Egger et al., 2004). It is well known that epigenetics plays a crucial role in gene regulation, growth and especially in development (Bird, 2007). Any alterations in epigenetic state
Epigenetic therapy
The initial thinking behind developing epigenetic therapies is that if it is possible to chemically manipulate factors such as methylation, acetylation etc., then it may be possible to alter regions where aberrant changes have taken place in order to try and restore the original state. Many agents capable of altering both methylation and acetylation have been discovered, and the applications of these are currently being tested (Egger et al., 2004). Agents include 5-azatine,
Rationale for investigation
Several lines of evidence exist to suggest that mitochondrial dysfunction may contribute to the pathogenesis of at least some subtypes of migraine. The brain and muscle are highly dependent on oxidative metabolism and are therefore the most severely affected tissues in the mitochondrial disorders. A variety of morphological, biochemical, imaging and genetic studies have provided evidence that mitochondrial dysfunction may play a role in migraine susceptibility (Sparaco et al., 2006). A
Mitochondrial methylation
Research interests in the relationship between nuclear DNA methylation, environmental exposures and disease outcome are well established. Epigenetic profiling has already become integrated into clinical practise for early diagnosis of cancer and as a molecular tool for determining cancer stages (Dehan et al., 2009, Laird, 2003). Bisulphite sequencing and methylated DNA immunoprecipitation in peripheral blood have been used to demonstrate the presence of methylated cytosines in the human D-loop
A multi-layered approach
For complex diseases where both a genetic and environmental component plays an integral role in pathogenesis, it is becoming more important to develop models which factor in both of these components. Epigenetic changes which are so heavily influenced by the environment have been intricately studied in the nuclear genome. Recent evidence directly suggests a link between nuclear epigenetic changes and migraine and indirectly suggests that the emerging field of mitochondrial methylation could
Conflict of interest
The authors declare that there is no conflict of interest.
Acknowledgements
Shani Stuart is the recipient of a QUT HDR Tuition Fee Sponsorship and QUT Postgraduate Research Award (QUTPRA) Scholarship for tuition fees and living allowance.
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