AUTHOR=Narwal Sonia , Singh Amit , Tare Meghana 

TITLE=Analysis of α-syn and parkin interaction in mediating neuronal death in Drosophila model of Parkinson's disease

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=17

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2023.1295805

DOI=10.3389/fncel.2023.1295805

ISSN=1662-5102

ABSTRACT=<p>One of the hallmarks of Parkinson's Disease (PD) is aggregation of incorrectly folded α-synuclein (<italic>SNCA</italic>) protein resulting in selective death of dopaminergic neurons. Another form of PD is characterized by the loss-of-function of an E3-ubiquitin ligase, <italic>parkin</italic>. Mutations in <italic>SNCA</italic> and <italic>parkin</italic> result in impaired mitochondrial morphology, causing loss of dopaminergic neurons. Despite extensive research on the individual effects of <italic>SNCA</italic> and <italic>parkin</italic>, their interactions in dopaminergic neurons remain understudied. Here we employ <italic>Drosophila</italic> model to study the effect of collective overexpression of <italic>SNCA</italic> along with the downregulation of <italic>parkin</italic> in the dopaminergic neurons of the posterior brain. We found that overexpression of <italic>SNCA</italic> along with downregulation of <italic>parkin</italic> 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 <italic>SNCA</italic> and downregulation of <italic>parkin</italic> 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 <italic>SNCA</italic> overexpression causes transcriptional downregulation of <italic>parkin</italic>. However, this downregulation is not further enhanced upon collective <italic>SNCA</italic> overexpression and <italic>parkin</italic> downregulation. This suggests that the interactions of <italic>SNCA</italic> and <italic>parkin</italic> may not be additive. Our study thus provides insights into a potential link between α<italic>-synuclein</italic> and <italic>parkin</italic> 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.</p>