The widespread fruit fly for more than a century, Drosophila melanogaster has been utilized as a genetic model system. Drosophila has been used to develop a vast array of genetic innovations during the past century because they are easy to keep and reproduce quickly. Drosophila is a good model for research into the cellular and molecular mechanisms underlying development and illness because they have plenty of genetic similarities with humans. In the past three decades, several human disorders, many of which damage the neurological system, have also been modeled in Drosophila1.

The complex nervous system of Drosophila contains many components that are similar to those of our nervous system: including eyes, olfactory organs, gustatory organs, auditory organs, a ventral nerve cord (analogous to the spinal cord), peripheral sensory neurons for proprioception and pain, and a brain. Additionally, the generation of enormous mutant collections that affect neural development facilitates the study of Drosophila. Moreover, several rigorous tests for measuring neurodegeneration in Drosophila may be employed, offering accurate measures for the effect of the disease process1.

The possibility that crucial pathogenetic elements are vertebrate-specific and could be overlooked in invertebrate models is a clear problem of utilizing fly models. For instance, Drosophila melanogaster cannot provide a good model for immunological illnesses like multiple sclerosis. Drosophila lacks vasculature and has a limited range of blood cells, primarily primitive hemocytes, making it unable to study brain infarcts and hemorrhages. Although one must keep in mind that the distinctions between mammals and invertebrates provide significant challenges in modeling brain disorders, most Drosophila models do replicate certain characteristics of human diseases2.
Neurodegeneration
Parkinson’s Disease
Parkinson’s disease (PD) is a prevalent neurodegenerative condition characterized by the progressive and selective loss of dopaminergic neurons. This illness has both genetic and environmental risk factors. About 20 genes, including SNCA, parkin, PTEN-induced kinase 1 (pink1), leucine-rich repeat kinase 2 (LRRK2), ATP13A2, MAPT, VPS35, and DJ-1, make up the genetic factors, while oxidative stress-induced toxins like 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), rotenone, and paraquat make up the environmental3.

It has been shown that these elements contribute to oxidative damage and mitochondrial dysfunction by analyzing their roles and processes, which has given vital new insights into the disease process. Studies employing disease model species, including fruit flies, worms, and mice, have shown to be the most fruitful. Among these, Drosophila melanogaster has distinguished itself as a superb model organism to investigate environmental and genetic variables and give insights into the pathways important for PD pathogenesis, supporting the development of treatment approaches3.
Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common irreversible cause of dementia. More than 24 million people worldwide suffer from it, which is characterized by increasing neurodegeneration and cognitive impairment. The healthcare sector is destined to suffer as a result of the condition as AD diagnoses are on the rise and put a strain on the system’s current support structures. In order to make a conclusive diagnosis of AD, extracellular amyloid plaques and intracellular neurofibrillary tangles must be correctly identified as neuropathological hallmarks. The transmembrane receptor Amyloid Precursor Protein is cleaved differently by proteases to produce amyloid-peptides (A), which make up the majority of plaques (APP). The endoproteolysis is performed by the β-site APP cleaving enzyme (BACE) and γ-secretases, consisting of Presenilin 1/2, Nicastrin, APH-1, and PEN-24.

Drosophila melanogaster models that address Tau or amyloid toxicity have been created to examine the underlying pathophysiology of AD. Tau overexpression in humans causes age-dependent neurodegeneration, axonal transport abnormalities, and premature mortality. Several kinases and phosphatases, apoptotic regulators, and cytoskeleton proteins have been discovered as determinants of Tau toxicity in vivo in large-scale screens using a neurodegenerative phenotype caused by eye-specific overexpression of human Tau. The Drosophila APP ortholog (dAPPl) shares the same domains as vertebrate APP family members but lacks the human Aβ42 domain. To overcome this limitation, researchers have created techniques that use the either direct secretion of human Aβ42 or triple transgenic flies expressing human APP, β-secretase, and Drosophila γ-secretase presenilin (dPsn)4. AD may be simulated in Drosophila using all available information.
Metabolic disorders
Nieman-Pick-Disease
Niemann-Pick disease is one of several lysosomal lipid storage diseases. Niemann-Pick type C (NPC) is an autosomal-recessive disease with a wide range of symptoms that manifest themselves from the prenatal period through adulthood. Cerebellar ataxia, dysarthria, dysphagia, seizures, and progressive dementia are all major neurological signs5. The buildup of cholesterol, glycosphingolipids, and other lipids characterizes NPC. Mutations in NPC1 or NPC2 produce an organelle trafficking deficiency and a lack of lipid homeostasis. NPC is distinguished histologically by the gradual loss of neurons, notably Purkinje cells in the cerebellum, lipid storage, the creation of meganeurites and ectopic dendrites, and the appearance of neurofibrillary tangles.
NPC1a null alleles in Drosophila die at an early larval stage, however giving NPC1a mutants the steroid hormone enhances longevity, indicating that NPC1a loss leads to decreased ecdysone production. Excess cholesterol compound feeding enhances lifespan till adulthood. Another Drosophila dnpc1a model exhibited sterol buildup, similar to human illness. The life expectancy of dnpc1a mutants might be prolonged till maturity by treating them with 7-dehydrocholesterol. The brain morphology was ordinary, with no signs of neurodegeneration. Another research utilizing the identical dnpc1a mutants found neuronal cholesterol deposits, the buildup of multilamellar structures, and age-dependent vacuolization. Age-dependent neurodegeneration, early mortality, and mobility abnormalities may all be totally or partially reversed by neuronal and glial expression of the wild-type dNPC1a transgene6. Npc2a mutants have a shortened life span but no evidence of brain vacuolization. TUNEL labeling identified apoptotic neurons. NPC can be effectively mimicked in Drosophila since the disease’s cholesterol storage and neurodegenerative components are represented2.
It is now necessary to take into account a variety of Drosophila models for neurodegenerative and metabolic brain disorders to compare and contrast invertebrate and rodent models of human disease. Thanks to genetic techniques, large modifier screens will be able to identify possible pathways and interactions, which may throw light on as-yet-unknown disease processes. The discovery of genes that control disease processes in the brain in Drosophila screens has to be supported by higher model species to uncover viable therapies for human diseases.
References:
- Bolus H, Crocker K, Boekhoff-Falk G, Chtarbanova S. Modeling Neurodegenerative Disorders in Drosophila melanogaster. Int J Mol Sci 2020, Vol 21, Page 3055. 2020;21(9):3055. doi:10.3390/IJMS21093055
- Jeibmann A, Paulus W. Drosophila melanogaster as a Model Organism of Brain Diseases. Int J Mol Sci. 2009;10:407-440. doi:10.3390/ijms10020407
- Aryal B, Lee Y. Disease model organism for Parkinson disease: Drosophila melanogaster. BMB Rep. 2019;52(4):250. doi:10.5483/BMBREP.2019.52.4.204
- Prüßing K, Voigt A, Schulz JB. Drosophila melanogaster as a model organism for Alzheimer’s disease. Mol Neurodegener. 2013;8(1):1-12. doi:10.1186/1750-1326-8-35/FIGURES/2
- Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003;64(4). doi:10.1034/j.1399-0004.2003.00147.x
- Phillips SE, Woodruff EA, Liang P, Patten M, Broadie K. Neuronal loss of Drosophila NPC1a causes cholesterol aggregation and age-progressive neurodegeneration. J Neurosci. 2008;28(26). doi:10.1523/JNEUROSCI.5529-07.2008
Figure References:
- Dhankhar J, Agrawal N, Shrivastava A. An interplay between immune response and neurodegenerative disease progression: An assessment using Drosophila as a model. J Neuroimmunol. 2020;346. doi:10.1016/j.jneuroim.2020.577302
- Dhankhar J, Agrawal N, Shrivastava A. An interplay between immune response and neurodegenerative disease progression: An assessment using Drosophila as a model. J Neuroimmunol. 2020;346. doi:10.1016/j.jneuroim.2020.577302
- Sanz FJ, Solana-Manrique C, Muñoz-Soriano V, Calap-Quintana P, Moltó MD, Paricio N. Identification of potential therapeutic compounds for Parkinson’s disease using Drosophila and human cell models. Free Radic Biol Med. 2017;108. doi:10.1016/j.freeradbiomed.2017.04.364
- Tue NT, Dat TQ, Ly LL, Anh VD, Yoshida H. Insights from Drosophila melanogaster model of Alzheimer’s disease. Front Biosci – Landmark. 2020;25(1). doi:10.2741/4798
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