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Investigation of the Contribution of Copy Number Alterations in Parkinson’s Disease Genes to Pathogenesis

In most cases, the cause of Parkinson’s disease (PD) is unknown. Testing blood for DNA mutations is usually negative, but there is increasing evidence that DNA can mutate during normal development (after conception). These “somatic” mutations could be present only in a proportion of brain cells. We will investigate DNA from brain for evidence of somatic mutations that have led to a change in the number of copies of relevant genes, focusing on alpha-synuclein.

Project Description:             
We will first focus on three brain regions from 20 PD patients and five controls, including the substantia nigra. We will use a custom-designed microarray (laboratory technology for gene study), which we expect to be able to detect a 10 percent change in the level of DNA for alpha-synuclein and our other target genes. This change would result from one in five cells having an extra or missing copy of that gene. If we find evidence of this, we will confirm it with other methods, and screen more patients and controls. If there is no evidence, we will investigate the possibility that only a small percentage of cells have an extra copy of alpha-synuclein. We will use a technique called fluorescent in situ hybridization (FISH), which allows us to directly visualize the gene in the cell nucleus. 

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Evidence of somatic mutations in PD will indicate that PD can result from changes in the genes, even without a family history. This would suggest that tests to detect somatic mutations should be done using DNA from tissues that are more closely related to the brain than the blood. Detection of such somatic mutations, which could lead to PD later in life, could allow earlier treatment when preventative drugs are available.

Anticipated Outcome:          
We will provide the first data on whether changes in the number of copies of alpha-synuclein and other relevant genes exist in the brain as a result of “somatic” DNA mutations. A positive result will provide a totally new avenue of research into the causes of PD, and additional opportunities for testing, while a negative result will imply that such mutations are unlikely to be common.

Final Outcome

In this study, we aimed to detect changes in certain genes, such as SNCA, a gene that regulates the production of alpha-synuclein, a sticky protein that clumps in the brains of people with Parkinson's disease (PD). We have completed the analysis of DNA from one to three brain regions of over 25 people with Parkinson's and 10 healthy people. For this analysis, we used our custom microarray, a technology that allows for analysis of thousands of genes on a single glass slide. We found multiple copies of SNCA in the substantia nigra -- a brain region involved in PD -- of people with Parkinson's. This increase in the number of SNCA gene copies in the substantia nigra but not in other areas of the brain could potentially explain why brain cells in the substantia nigra are susceptible to neurodegeneration in PD. Additional analysis is needed to confirm these findings.

We have also developed and tested a technology that allows us to image (view) SNCA and PRKN, two genes linked to PD, inside the cell. We have already imaged the SNCA gene in several brain tissue samples, and we are currently analyzing our results.

September 2014


  • Ellie Nacheva, MD, PhD

    London United Kingdom

  • Anthony Schapira, MD, DSc, FRCP, FMedSci

    London United Kingdom

  • Christos Proukakis, BM BCh, PhD

    London United Kingdom

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