Analysis of α-syn and interaction in mediating neuronal death in model of Parkinson's disease.

One of the hallmarks of Parkinson's Disease (PD) is aggregation of incorrectly folded α-synuclein () protein resulting in selective death of dopaminergic neurons. Another form of PD is characterized by the loss-of-function of an E3-ubiquitin ligase, . Mutations in and result in impaired mitochondrial morphology, causing loss of dopaminergic neurons. Despite extensive research on the individual effects of and , their interactions in dopaminergic neurons remain understudied. Here we employ model to study the effect of collective overexpression of along with the downregulation of in the dopaminergic neurons of the posterior brain. We found that overexpression of along with downregulation of causes a reduction in the number of dopaminergic neuronal clusters in the posterior region of the adult brain, which is manifested as progressive locomotor dysfunction. Overexpression of and downregulation of collectively results in altered mitochondrial morphology in a cluster-specific manner, only in a subset of dopaminergic neurons of the brain. Further, we found that overexpression causes transcriptional downregulation of . However, this downregulation is not further enhanced upon collective overexpression and downregulation. This suggests that the interactions of and may not be additive. Our study thus provides insights into a potential link between α and interactions. These interactions result in altered mitochondrial morphology in a cluster-specific manner for dopaminergic neurons over a time, thus unraveling the molecular interactions involved in the etiology of Parkinson's Disease.