Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism

Abstract

Background Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder marked by the death of nigrostriatal dopaminergic neurons in response to the compounding effects of oxidative stress, mitochondrial dysfunction and protein aggregation. Transgenic Drosophila models have been used extensively to decipher the underlying genetic interactions that exacerbate neural health in PD. Autosomal recessive forms of the disease have been linked to mutations in the serine/threonine kinase PINK1(PTEN-Induced Putative Kinase 1) and E3 ligase Parkin, which function in an axis that is conserved in flies. This review aims to probe the current understanding of PD pathogenesis via the PINK1/Parkin axis while underscoring the importance of several molecular and pharmacologic rescues brought to light through studies in Drosophila. Main body Mutations in PINK1 and Parkin have been shown to affect the axonal transport of mitochondria within dopaminergic neurons and perturb the balance between mitochondrial fusion/fission resulting in abnormal mitochondrial morphology. As per studies in flies, ectopic expression of Fwd kinase and Atg-1 to promote fission and mitophagy while suppressing fusion via MUL1 E3 ligase may aid to halt mitochondrial aggregation and prolong the survival of dopaminergic neurons. Furthermore, upregulation of Hsp70/Hsp90 chaperone systems (Trap1, CHIP) to target misfolded mitochondrial respiratory complexes may help to preserve their bioenergetic capacity. Accumulation of reactive oxygen species as a consequence of respiratory complex dysfunction or antioxidant enzyme deficiency further escalates neural death by inducing apoptosis, lipid peroxidation and DNA damage. Fly studies have reported the induction of canonical Wnt signalling to enhance the activity of transcriptional co-activators (PGC1α, FOXO) which induce the expression of antioxidant enzymes. Enhancing the clearance of free radicals via uncoupling proteins (UCP4) has also been reported to ameliorate oxidative stress-induced cell death in PINK1/Parkin mutants. Conclusion While these novel mechanisms require validation through mammalian studies, they offer several explanations for the factors propagating dopaminergic death as well as promising insights into the therapeutic importance of transgenic fly models in PD.

Mitochondria-Related Apoptosis Regulation by Minocycline: A Study on a Transgenic Drosophila Model of Alzheimer’s Disease

“…Analyzing the reduced jumping performance in transgenic AD flies revealed the severity of Aβ42 in the brain. As shown in Figure 1B, a significant reduction was observed in transgenic AD flies [F (4,20) , p < 0.001, q = 25.69] when compared to control flies. However, after 30 days of exposure to 870 μM minocycline, transgenic AD flies showed a significant mitigating effect on jumping behavior with reference to unexposed transgenic AD flies (p < 0.05, q = 6.39).…”

“…We conducted the survival experiment in all of the groups to further corroborate our findings. When compared to control flies, the survival of transgenic AD flies was significantly reduced (F (4,20) , p < 0.01) (Figure 2). Therefore, we exposed transgenic AD flies to an 870 μM concentration of minocycline, based on the feeding schedule.…”

“…The severity of Aβ42 aggregation in flies' brain tissue correlates well with the phenotype of locomotory performance decline. After the 30th day, transgenic AD flies showed a significant reduction [F (4,20) , p < 0.001, q = 16.32] in locomotion as compared to control flies (Figure 1A). However, 870 μM minocycline exposure of AD flies for 30 days showed a significant enhancement in climbing behavior (p < 0.01, q = 12.97) as compared to transgenic AD flies.…”

“…Also, previous studies suggested that minocycline has potential to prevent the formation of the Aβ monomer to an oligomer in ex vivo and in vivo models of AD. Available studies suggested that minocycline prevents the death of neurons by inhibiting the formation of pores in mitochondria in various neurodegenerative diseases. , Based on these previous findings, the present study aims to find out whether minocycline can preserve the integrity of mitochondria and helps to maintain the neuron functions and survival in a transgenic Drosophila AD model. Drosophila is a well-known genetic model in the area of AD research to explore the potential targets and screening of a pharmacological agent in the search of effective drugs against AD .…”

Psychosis in Parkinson’s Disease: A Lesson from Genetics

“…The second common gene responsible for autosomal recessive forms of PD is PINK1 , which encodes a mitochondrial serine–threonine kinase able to trigger the phosphorylation-dependent activation of Parkin, maintaining its mitochondrial stabilization and translocation to damaged mitochondria [ 37 , 38 ]. The majority of mutations in PINK1 induce conformational changes in its catalytic domains leading to loss of kinase activity and the subsequent block of Parkin translocation for mitochondrial quality check [ 39 ]. After the PRKN - and PINK1 -related cases, biallelic variants in DJ-1 have been linked to a rare form of autosomal recessive PD with early onset.…”