The Importance of Drosophila melanogaster Research to UnCover Cellular Pathways Underlying Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a complex neurodegenerative disorder that is currently incurable. As a consequence of an incomplete understanding of the etiology of the disease, therapeutic strategies mainly focus on symptomatic treatment. Even though the majority of PD cases remain idiopathic (~90%), several genes have been identified to be causative for PD, facilitating the generation of animal models that are a good alternative to study disease pathways and to increase our understanding of the underlying mechanisms of PD. Drosophila melanogaster has proven to be an excellent model in these studies. In this review, we will discuss the different PD models in flies and key findings identified in flies in different affected pathways in PD. Several molecular changes have been identified, of which mitochondrial dysfunction and a defective endo-lysosomal pathway emerge to be the most relevant for PD pathogenesis. Studies in flies have significantly contributed to our knowledge of how disease genes affect and interact in these pathways enabling a better understanding of the disease etiology and providing possible therapeutic targets for the treatment of PD, some of which have already resulted in clinical trials.

Neurodegenerative Disorders: Spotlight on Sphingolipids

“…However, similar mechanisms are present in both sporadic and genetic forms of the disease. Studies on drug abusers with parkinsonism have hinted towards defects at the level of the mitochondrial electron transport chain, which was later confirmed in patients and animal models [ 66 , 67 , 68 , 69 , 70 ]. Furthermore, PINK1-dependent phosphorylation is required for an efficient ETC, and the stimulation of the ETC can alleviate signs in pink1- and drug-related PD animal models [ 71 , 72 , 73 ].…”

“…Interestingly, mitochondrial symptoms have been observed in other genetic PD models, including alpha-synuclein-dependent models [ 79 ], suggesting that mitochondrial dysfunction plays an important role in the pathogenesis of PD; however, the underlying mechanisms of how mitochondrial dysfunction results in neurodegeneration remains enigmatic. A more recently identified pathway that is linked to PD is the endo-lysosomal pathway, in which the autosomal dominant PD-related genes play a major role [ 70 ]. Alpha-synuclein and LRRK2 are linked to Rab proteins, which are important in the endo-lysosomal pathway [ 80 , 81 ].…”

Chronic Exposure to Paraquat Induces Alpha-Synuclein Pathogenic Modifications in Drosophila

“…Although non-human primates most closely mimic the human pathology, mice are the most often used animal model [ 11 ]. The neuronal overexpression of human αSyn in mouse neurons can be associated with αSyn aggregation and locomotor impairment although the loss of dopaminergic neurons is often not observed [ 12 ]. For example, it was shown that misfolded and hyperphosphorylated αSyn that are resistant to proteinase K digestion are found in transgenic mice with motor deterioration [ 6 ].…”

“…Several models of PD were developed in Drosophila , including a well-characterized model in which the neuronal overexpression of human SNCA gene using the UAS/GAL4 system mimics PD hallmarks [ 19 ]. This model was greatly used to study and characterize conserved cellular mechanisms associated with αSyn pathology in humans, despite the fact that Drosophila does not carry an endogenous ortholog of SNCA gene [ 12 , 20 , 21 ]. The common parkinsonian hallmarks observed in flies overexpressing SNCA include the accumulation of αSyn aggregates in situ, loss of dopaminergic neurons (DA), and the impairment of fly locomotion (negative geotaxism) [ 17 , 19 , 22 , 23 , 24 ].…”

Mitochondrial Complex I deficiency: guilty in Parkinson’s disease

“…Notwithstanding, in the last few decades, immense research efforts have revealed several mechanisms that are affected in PD, including mitochondrial abnormalities. 3 …”