Available genetic information in Parkinson's disease does not account for all phenomena in the clinical expressivity of the disease. For example, in the Contursi kindred with the A53T substitution in alpha-synuclein, the variation of onset age, which is taken as an index of disease aggressiveness, mirrors that of sporadic disease, ranging between 20 years and 86 years. This suggests that reasons other than the mutation in alpha-synuclein dictate the rate of neuronal degeneration and hence onset age. This observation raises the suspicion that factors other than genetic determinants based on inherited DNA sequence changes contribute to PD.
The goal of this project is to study why individuals in the Contursi kindred manifest PD at different ages. Based on the known deleterious effects of excess alpha-synuclein in humans and animal models, we hypothesize that the degree of expression of the alpha-synuclein gene can be an index or biomarker of disease susceptibility. We postulate that increased transcription rate of the alpha-synuclein gene accelerates the neurodegenerative process and, therefore, results in an earlier symptom manifestation. Epigenetic factors including the status of DNA methylation leading to changes in chromatin structure are powerful regulatory mechanisms in controlling gene expression, and can account for stable and potentially heritable changes.
We propose to investigate the DNA methylation status of the alpha-synuclein gene in individuals from the Contursi kindred and assess the correlation between this outcome measure and age at symptom onset. If a correlation is established between the methylation of peripheral blood DNA and disease onset age, this test can be applied to other PD populations who do not have mutations in the alpha-synuclein gene as a biomarker of disease susceptibility.
Final Outcome
Dr. Mouradian was given a small pilot award to test the state of epigenetic regulation of the alpha-synuclein gene in humans. This was a high-risk project due to its novelty. MJFF funded Dr. Mouradian to extend her initial observations and gather additional evidence for her hypothesis. Preliminary data supported by this award showed that this gene is methylated at specific sites. It would be of interest for future studies to extend this finding to a larger sample size.