This project laid the foundation for the identification of new therapeutic targets for Parkinson’s disease (PD). PD, which was first described in detail in An Essay on the Shaking Palsy by James Parkinson, is strongly associated with progressive loss of dopaminergic neurons during aging and affects more than 10 million people worldwide over 65 years of age. The pathological hallmark of PD is the Lewy body, consisting largely of aggregated alpha-Synuclein. The abnormal distribution of alpha-Synuclein correlates with neurodegeneration, which is seen in several PD models, including a roundworm Caenorhabditis elegans, a powerful model organism for aging research that has helped us to understand the development of proteinopathy. Only 10% of diagnosed PD patients have familial history with identified genetic variations affecting common cellular mechanisms responsible for cell protection during stress. Pathogenic mutations have been identified in genes responsible for protein and organelle quality control machineries amongst others, such as Parkin. On the other hand, sporadic PD does not have a clear mechanism of development and, therefore, it is considered a complex disease with multifactorial etiology. Several genome-wide association studies (GWAS) have identified several tens of risk signals associated with sporadic PD that are surrounded by hundreds of susceptibility genes. To date, there is little to no published functional validation of genes in these loci.
As the incidence of PD increases with age (with estimated 4% prevalence over 85 years of age), the rapidly growing lifespan of human population is a huge economic and social burden for society. Current therapeutic interventions only alleviate symptoms but do not halt disease progression or induce neuro-restoration. Identifying novel molecular targets and searching for therapeutic agents that block neurodegeneration and promote neuronal restoration is a key challenge in the field.
This project aimed to use a roundworm C. elegans, as an animal model, to identify genes modulating pathology associated with Parkinson’s disease (Objective 1), and subsequently elucidate the conservation of the newly identified genetic components in human cell-based model systems (Objective 2).
Firstly, a new model (eraIs1) was constructed with a fluorescent alpha-synuclein construct. The obtained data using eraIs1, identified 28 C. elegans genes that modulated neurotoxicity caused by human alpha-Synuclein and genes that regulated the abundance of Parkin (the major cause of autosomal recessive juvenile parkinsonism). Subsequent evaluation of some of these genes on PD pathogenesis in human cell model systems suggested that genes regulating intracellular calcium levels could modulate alpha-Synuclein pathology. These data indicate that they might play a role in the pathogenesis of PD. This project thus provided both a new C. elegans model for PD gene screening, and identified new potential therapeutic targets for aging-related neurodegenerative diseases, and should therefore also bring forth an understanding of pathology in PD.
