A succinct, lay-oriented statement of the scientific rationale for this project. We have recently shown that genetic variants at the SNCA gene locus, coding for the alpha-synuclein protein, confer increased risk of Parkinson’s disease (PD) and multiple system atrophy (MSA). To further explore the haplotype structure at the SNCA locus in these two related disorders, we propose to perform haplotype fine-mapping using massively parallel sequencing in pathology-proven cases with PD, with MSA or in normal controls.
We will capture the entire SNCA locus, including introns and regulatory regions, using a custom-designed capture library, followed by massively parallel next-generation sequencing in separate pools of DNA samples from pathology-proven MSA cases, pathology-proven PD cases and pathology-proven normal controls. Detailed haplotype maps will be reconstructed for each individual.
Relevance to Diagnosis/Treatment of Parkinson’s Disease
We plan to investigate whether the haplotype structure at the SNCA locus allows us to differentiate individuals with multiple system atrophy from individuals with Parkinson’s disease and from normal controls. Further, we will be able to detect variants in non-coding, regulatory regions that might have been missed in previous screening studies. Detailed information on genetic variability and the haplotype structure at this crucial risk locus could provide new insights into the pathogenesis of PD and MSA.
We anticipate one of two possible outcomes. Firstly, the alleles (either singularly or in the form of a haplotype) associated with PD and MSA may be identical. The second outcome is that there are distinct variations in the haplotypes associated with PD and with MSA. Such a finding might provide fundamental insight into why synuclein is deposited predominantly within neurons in PD and within glia in MSA.