Abstract
ObjectiveSequestosome 1 (p62/SQSTM1) is a multifunctional scaffold/adaptor protein encoded by the p62/SQSTM1 gene with function in cellular homeostasis. Mutations in the p62/SQSTM1 gene have been known to be associated with patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson disease (PD). The aim of the present study was to create a novel model of human neurogenerative disease in Drosophila melanogaster by altering the expression of Ref(2)P, the Drosophila orthologue of the human p62/SQSTM1 gene. Ref(2)P expression was altered in all neurons, the dopaminergic neurons and in the motor neurons, with longevity and locomotor function assessed over time.ResultsInhibition of Ref(2)P resulted in a significantly increased median lifespan in the motor neurons, followed by a severe decline in motor skills. Inhibition of Ref(2)P in the dopaminergic neurons resulted in a significant, but minimal increase in median lifespan, accompanied by a drastic decline in locomotor function. Inhibition of Ref(2)P in the ddc-Gal4-expressing neurons resulted in a significant increase in median lifespan, while dramatically reducing motor function.
Highlights
The elucidation of the cellular mechanisms that are altered during the progression of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD), is an ongoing subject of current research
Inhibition of Ref(2)P in the motor neurons increases longevity and reduces locomotor ability The inhibition of Ref(2)P via the UAS-Ref(2)P-Ribonucleic acid interference (RNAi) HMS00551 transgene through D42-Gal4 resulted in a significant increase in median lifespan by approximately 22%
We found that the inhibition of the Ref(2)P gene results in a significant increase in median lifespan, accompanied by a severe reduction in locomotor function over time
Summary
The elucidation of the cellular mechanisms that are altered during the progression of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD), is an ongoing subject of current research. The p62/SQSTM1 protein is localized throughout the cell in the cytoplasm, in the cytosol, and the endoplasmic reticulum, among other places such as autophagosomes, aggresomes, and autolysosomes, as this protein functions during the process of autophagy [4, 5]. The role which p62/SQSTM1 has in autophagy is critical as it seems to regulates the removal of protein aggregates and damaged organelles through the activities of several of its many functional domains [3]. The p62/ SQSTM1 protein has many functional domains, several of which are essential to autophagic activities. These domains include the Phox and Bem (PB1) domain, the LC3 interacting region (LIR) domain, and the UBA
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