Does DNA methylation hold the key to Parkinson’s Disease?

nigel williams Dr Nigel Williams is a Reader in molecular genetics at the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University. His research has identified genetic loci that increase risk to schizophrenia, ADHD and frontotemporal dementia. Currently he leads a research team focused on gaining a better understanding of neurological disorders, in particularly Parkinson’s Disease.

E: WilliamsNM@cardiff.ac.uk

The reasons we develop Parkinson’s Disease (PD) are complex. As in diseases such as rheumatoid arthritis and type-2 diabetes, the large majority of cases appear to be caused by a combination of genetic and environmental risk factors.

So far, a number of changes have been identified in the DNA of patients with a strong family history of PD that either lead to, or greatly increase the chances of developing the disease.These findings have greatly improved our understanding of the disease process. However, as these DNA changes are very rare, they collectively account for less than 5% of cases of PD.

The DNA changes that underlie PD in cases where there is not a strong family history of the illness have proved more elusive. In the last decade this problem has been tackled by a number of large-scale studies. These studies have collectively identified DNA alterations at more than 18 locations in our genome that increase our risk of developing the form of the illness that accounts for 95% of PD cases. However, little is known about how these DNA changes increase risk to disease. As most do not directly affect gene function, it is likely that they increase risk through more subtle biological mechanisms than those seen in rare inherited cases of the disease.

What is DNA Methylation

DNA methylation (DNAm) is an important, well-characterised chemical modification to DNA that influences gene function without changing the DNA sequence. Rather like a light switch determines whether a bulb is on or off, DNAm can act as a molecular switch that regulates whether a gene is active or silenced (Figure 1).

nigel w figure 1

Importantly, we can now accurately measure DNAm, and this has allowed researchers to establish that we acquire changes in DNAm as we age, and that these can be influenced by environmental factors such as diet, smoking and exposure to toxins. Returning to our examples of rheumatoid arthritis and type-2 diabetes,research into these conditions has demonstrated a correlation between DNAm and DNA sequence changes that increase the risk of developing these diseases.

Changes in DNA Methylation can mediate risk to disease

The importance of DNAm in the causation and progression of cancer has also been well established by researchers. As these chemical modifications are potentially reversible, they have become the focus of novel anti-cancer therapies. If we can gain a similar understanding of the role of DNAm in PD, we may see similar gains.The neuropathology of PD is well understood, and good quality post mortem tissue is available, making PD particularly well suited to investigations of DNAm. But despite this, there have been few relevant studies.

DNA Methylation and Parkinson’s Disease?

At Cardiff University’s MRC Centre for Neuropsychiatric Genetics and Genomics, we have a research program examining the role that DNAm plays in the development of PD. We are doing this by collecting DNA from donated post-mortem tissue from regions of the brain known to be affected in PD (e.g. the substantia nigra). Our research takes in large numbers of PD patients and controls matched for age, sex and ethnicity. Using state-of-the-art technology, each DNA sample is being comprehensively assessed in a process that examines over 450,000 DNAm changes spanning the entire human genome.

We have hypothesised that the role of DNam might take three forms (Figure 2).

nigel w fig 2

Firstly, it is possible that changes in DNAm have an effect on the likelihood of developing PD for those who already carry a genetic risk of the disease.To investigate this, we will examine whether having PD genetic risk variants affects the accumulation of DNAm as we age,in turn affecting gene function and increasing risk of developing the disease.

Secondly, DNAm may increase risk of developing PD independently of an individual’s genetic risk.Age,diet,stress and toxins have already been correlated with the onset and severity of PD,and have also been shown to influence DNAm.By comparing changes in DNAm between PD and control samples we could take an important first step in establishing how environmental factors affect risk of developing the illness.

A final possibility is that changes in DNAm are just an inevitable consequence of the disease. If this is the case, it could be established by comparing PD patients at different stages of the disease.

Final Remarks

Identifying DNAm changes that either affect our risk of developing PD or are correlated with the way the disease progresses could have a major impact on the clinical diagnosis, prognosis and future treatment of PD.

Even more exciting is the fact that DNAm modifications and their related biological mechanisms are potentially reversible, and that drugs are already being developed to target these mechanisms in the brain.With this in mind, our research could help highlight new areas for the development of therapies for this devastating disease.