Objective/Rationale:
Genetic and environmental factors both have been linked to Parkinson’s disease (PD). Over the last 15 years, many PD susceptibility genes have been described. However, overall causal genetic variants have been detected in only 5-10 percent of PD cases, which leaves the vast majority of genetic contribution to PD still unexplained. Novel approaches are needed to unravel PD genes.
Project Description:
We apply a novel concept of gene discovery using gene copy number variant (CNV) analysis to identify novel candidate genes followed by gene sequencing to identify point mutations. CNVs are defined as structural changes of genetic material (DNA) consisting of losses or gains larger than 1000 bases pairs (building blocks). In the discovery phase, we already identified 20 candidate genes related to PD, related to, for example, binding partners, cellular processes, or molecular pathways for known PD genes. In this project we will genetically validate one particularly interesting candidate that is involved in mitochondrial function and highly relevant for PD pathogenesis. We will replicate the findings of the discovery phase in an independent PD cohort for this gene and functionally validate potentially pathogenic mutations in cellular models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The identification of novel PD disease genes can lead to several important advances for diagnosis and treatment of PD: 1) Underlying genetic cause is important for patients and scientists to understand disease 2) Mutations in genes can be targets for neuroprotective treatment (once available) that can begin before the onset of PD symptoms 3) New disease-causing genes can become new drug targets or related cellular pathways can be interrogated for drug discovery
Anticipated Outcome:
New candidate genes for PD need to be replicated in an independent cohort, the mutation spectrum needs be evaluated, and functional tests in cellular models are to be carried out to confirm if mutations in gene are truly causative of disease. In this study, we will determine if the proposed novel mitochondrial gene detected by CNV analysis is a new disease-causing or associated gene relevant for PD.