Functionally Validating Evolutionary Conserved Risk Genes for Parkinson's Disease in Drosophila melanogaster

Simple Summary The neurodegenerative disorder Parkinson's disease (PD) has a multifactorial etiology, and recent large-scale genetic studies have identified more than one hundred regions in the human genome that display statistical association with the risk of developing PD. To understand the disease mechanism better, biological validation of the identified genomic regions is warranted. However, in most studies such validation is absent. The aim of the study was to identify PD-genes that are evolutionary conserved between humans and the vinegar fly, and phenotypically investigate the effect of gene expression knockdown of those genes in the fly model. We identified eleven PD-genes that display strong evolutionary conservatism, and we successfully reduced gene expression in nine of the knockdown lines. A phenotype that previously has been used to investigate PD in a fly model is the flies' innate escape response. We found that gene expression knockdown resulted in a disrupted escape response in eight of the nine knockdown lines. These results provide additional support for potential involvement of these genes in the disease pathology underlying PD. Parkinson's disease (PD) is a heterogeneous and complex neurodegenerative disorder and large-scale genetic studies have identified >130 genes associated with PD. Although genomic studies have been decisive for our understanding of the genetic contributions underlying PD, these associations remain as statistical associations. Lack of functional validation limits the biological interpretation; however, it is labour extensive, expensive, and time consuming. Therefore, the ideal biological system for functionally validating genetic findings must be simple. The study aim was to assess systematically evolutionary conserved PD-associated genes using Drosophila melanogaster. From a literature review, a total of 136 genes have found to be associated with PD in GWAS studies, of which 11 are strongly evolutionary conserved between Homo sapiens and D. melanogaster. By ubiquitous gene expression knockdown of the PD-genes in D. melanogaster, the flies' escape response was investigated by assessing their negative geotaxis response, a phenotype that has previously been used to investigate PD in D. melanogaster. Gene expression knockdown was successful in 9/11 lines, and phenotypic consequences were observed in 8/9 lines. The results provide evidence that genetically modifying expression levels of PD genes in D. melanogaster caused reduced climbing ability of the flies, potentially supporting their role in dysfunctional locomotion, a hallmark of PD.

Automated summary

Parkinson's disease (PD) is a neurodegenerative disorder with a complex etiology, and genetic studies have identified over 100 genomic regions associated with the risk of developing PD. This study aimed to validate PD-associated genes in fruit flies and found 11 highly conserved genes between humans and fruit flies. Knockdown of these genes resulted in disrupted escape response in fruit flies, supporting their potential involvement in PD pathology.