Ameliorative influence of atorvastatin in transgenic Drosophila Melanogaster model of neurodegenerative diseases
Keywords:
α-synuclein, Aβ42, UAS-GAL4 system, lifespan, fecundityAbstract
Background: The common features in the pathogenesis of Alzheimer's disease (AD) and Parkinson disease (PD) (two most common neurodegenerative diseases) are chronic and progressive aggregation and accumulation of misfolded proteins (amyloid-beta and tau proteins in AD as well as α-synuclein in PD) leading to the destruction of vulnerable neurons and synaptic connections and ultimately neuronal cell death brain mass loss. Despite our knowledge of the molecular mechanisms implicated in AD and PD pathogenesis and primary target of therapeutic intervention being the misfolded protein aggregates, no effiffifficient treatments are available. The fruit flfly, Drosophila melanogaster (Drosophila), is a valuable model organism for neurodegenerative disease owing to its short lifespan and plethora of genetic tools for exquisite targeted manipulation of the genome. Thus, in this study the protective action of atorvastatin on genetic model of AD and PD in mice.
Methods: To model PD and AD in Drosophila, the bipartite system of GAL4 transcriptional activator was placed under a cell-type specifific promoter; embryonic lethal abnormal visual system GAL4 (ELAV-GAL4) or dopa decarboxylase (Ddc-GAL4) for expression of amyloid-beta (Aβ42) or α-synuclein, respectively, under the control of the upstream activating sequence (UAS) in Drosophila. The flflies were was either maintained on media supplemented with vehicle or atorvastatin (85, 170 or 340µM; HMG-CoA reductase inhibitor – antihyperlipidemic drug). The effffect of treatments on larva motility, climbing activity, fecundity and lifespan were recorded.
Results: Supplementation of flfly media with difffferent concentration of atorvastatin ameliorated the deficits in larva motility and climbing activity. Moreover, supplementation of flfly media with atorvastatin prolonged the survival of drosophila but atorvastatin (384µM) reduced fecundity.
Conclusion: Findings from this study showed that atorvastatin improved spontaneous motor activity and prolonged lifespan in Drosophila possibly through reduction of misfolded protein aggregates.
References
McGurk L, Berson A, Bonini NM. Drosophila as an In Vivo Model for Human Neurodegenerative Disease. Genetics. 2015 Oct;201(2):377-402. https://doi: 10.1534/genetics.115.179457.
Lenz S, Karsten P, Schulz JB, Voigt A. Drosophila as a screening tool to study human neurodegenerative diseases. J Neurochem. 2013;127(4):453-60. https://doi: 10.1111/jnc.12446.
Poirier L, Seroude L. Genetic approaches to study aging in Drosophila melanogaster. Age (Dordr). 2005 Sep;27(3):165-82. https://doi: 10.1007/s11357-005-2919-9.
Venken KJ, Simpson JH, Bellen HJ. Genetic manipulation of genes and cells in the nervous system
of the fruit fly. Neuron. 2011 Oct 20;72(2):202-30. https://doi: 10.1016/j.neuron.2011.09.021.
Li HH, Kroll JR, Lennox SM, Ogundeyi O, Jeter J, Depasquale G, Truman JW. A GAL4 driver resource
for developmental and behavioral studies on the larval CNS of Drosophila. Cell Rep. 2014 Aug 7;8(3):897-908. https://doi: 10.1016/j.celrep.2014.06.065.
Seroude L, Brummel T, Kapahi P, Benzer S. Spatio-temporal analysis of gene expression during aging in Drosophila melanogaster. Aging Cell. 2002 Oct;1(1):47-56. https://doi: 10.1046/j.1474-9728.2002.00007.x.
Chu LW, Chen JY, Yu KL, Cheng KI, Wu PC, Wu BN. Neuroprotective and anti-inflammatory activities of atorvastatin in a rat chronic constriction injury model. Int J Immunopathol Pharmacol. 2012;25(1):219-30. https://doi: 10.1177/039463201202500124.
Chen JH, Wu T, Xia WY, Shi ZH, Zhang CL, Chen L, Chen QX, Wang YH. An early neuroprotective effect
of atorvastatin against subarachnoid hemorrhage. Neural Regen Res. 2020 Oct;15(10):1947-1954.
https://doi: 10.4103/1673-5374.280326.
Lee ST, Chu K, Park JE, Hong NH, Im WS, Kang L, Han Z, Jung KH, Kim MW, Kim M. Atorvastatin
attenuates mitochondrial toxin-induced striatal degeneration, with decreasing iNOS/c-Jun levels and
activating ERK/Akt pathways. J Neurochem. 2008 Mar;104(5):1190-200. https://doi: 10.1111/j.1471-
2007.05044.x.
Lv F, Yang X, Cui C, Su C. Exogenous expression of Drp1 plays neuroprotective roles in the Alzheimer's disease in the Aβ42 transgenic Drosophila model. PLoS One. 2017 May 22;12(5):e0176183. https://doi: 10.1371/journal.pone.0176183.
Ismail MZ, Hodges MD, Boylan M, Achall R, Shirras A, Broughton SJ. The Drosophila insulin receptor
independently modulates lifespan and locomotor senescence. PLoSOne. 2015 May 28; 10(5): e0125312. https://doi: 10.1371/journal.pone.0125312.
Nouhaud P, Mallard F, Poupardin R, Barghi N, Schlötterer C. High-throughput fecundity measurements in Drosophila. Sci Rep. 2018;8(1):4469. https://doi:10.1038/s41598-018-22777-w
Barnes AI, Wigby S, Boone JM, Partridge L, Chapman T. Feeding, fecundity and lifespan in female
Drosophilamel anogaster. Proc Biol Sci. 2008; 275 (1643): 1675 - 83. https://doi:
1098/rspb.2008.0139.
Tastekin I, Khandelwal A, Tadres D, Fessner ND, Truman JW, Zlatic M, Cardona A, Louis M. Sensorimotor pathway controlling stopping behavior during chemotaxis in the Drosophila melanogaster larva. Elife. 2018;7: e38740. https://doi: 10.7554/eLife.38740.
Loveless J, Webb B. A Neuromechanical Model of Larval Chemotaxis. Integr Comp Biol. 2018 Nov
;58(5):906-914. https://doi: 10.1093/icb/icy094.
Ali YO, Escala W, Ruan K, Zhai RG. Assaying locomotor, learning, and memory deficits in Drosophila models of neurodegeneration. J Vis Exp. 2011;(49):2504. https://doi: 10.3791/2504.
Muscari A, Puddu GM, Santoro N, Serafini C, Cenni A, Rossi V, Zoli M. The atorvastatin during ischemic stroke study: a pilot randomized controlled trial. Clin Neuropharmacol. 2011;34(4):141-7. https://doi: 10.1097/WNF.0b013e3182206c2f.
Çelik H, Karahan H, Kelicen-Uğur P. Effect of atorvastatin on Aβ1-42 -induced alteration of SESN2,
SIRT1, LC3II and TPP1 protein expressions in neuronal cell cultures. J Pharm Pharmacol. 2020 Mar;72(3):424-436. https://doi: 10.1111/jphp.13208.
Soto C, Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci. 2018;21(10):1332-1340. https://doi: 10.1038/s41593-018-0235-9.
Spindler SR, Li R, Dhahbi JM, Yamakawa A, Mote P, Bodmer R, Ocorr K, Williams RT, Wang Y, Ablao KP. Statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation. PLoS One. 2012;7(6):e39581. https://doi: 10.1371/journal.pone.0039581.
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