Flight Paths to Understanding: Drosophila melanogaster as a Trailblazing

Model for Human Disease Exploration

Renier Joe C. Gamboa1, Daniella Mae G. Guiang1, Ruby Claire S. Lay-on1 & Jesilea C.
Ramoran1
1
Biological and Physical Sciences Department, College of Arts and Sciences
Don Mariano Marcos Memorial State University -South La Union Campus
Agoo, La Union

Introduction affordability, quick reproductive cycle, and

During the late 20th and early 21st robust genetic resources have rendered it
centuries, classical cell line and animal indispensable for over a century in
model systems were successfully used in fundamental scientific inquiries. With the
biomedical research. These uses included integration of numerous molecular
advancing our knowledge of cellular techniques, this model organism has
signaling pathways, locating possible drug continuously adapted to keep pace with
targets, and directing the development of cutting-edge advancements. This edition
candidate drugs for diseases like cancer and features various authors showcasing
infectious diseases. The fact that these contemporary applications of Drosophila
model systems are now almost always used and speculating on its future trajectories.
in biomedical research is evidence of the From its role in mimicking human diseases
importance of the advancements they have to unraveling the intricacies of cellular
made possible. A common discovery structure and function, as well as exploring
pipeline has historically been followed by behavior and aging, this publication delves
researchers studying disease mechanisms in into the diverse applications of fruit flies and
animal models: biological processes were their impact on other model organisms
first studied using genetic screens in (Tolwinski, 2017). It is utilized as a model
invertebrates, then evolutionary organism for a variety of scientific areas,
conservation was examined in mammalian including basic genetics and the
model systems, and finally clinical development of tissues and organs. About
translation to humans. Numerous human 75% of the genes causing human disorders
diseases have a thorough mechanistic have homologs in flies, while the genomes
knowledge thanks to the shared principles of of drosophila and humans are 60% and less
animal development and organ physiology redundant, respectively (Ugur et al., 2016).
that resulted from this method (Kim et al., These characteristics, along with the fruit
2020). One of the common animal models fly's short generation time, cheap
used in research to study human diseases is maintenance requirements, and accessibility
Drosophila melanogaster. to potent genetic tools, make it possible to
The fruit fly, scientifically referred to investigate intricate pathways important to
as Drosophila melanogaster, holds a scientific research, including cancer. Indeed,
prominent status as a widely utilized model throughout the past ten years, the number of
organism in biomedical research. Its
articles using flies as cancer models has The Drosophila genome is
skyrocketed (Mirzoyan et al., 2019). approximately 180 Mb in size, with one-
Animal models play a crucial role in third of this being centric heterochromatin.
deciphering the mechanisms of diseases. By The 120 Mb of euchromatin is distributed
genetically altering animals or exposing across two large autosomes and the X
them to disease-causing agents, researchers chromosome, while the small fourth
can examine the pathophysiology of diseases chromosome contains only about 1 Mb of
in a controlled setting (Jankowsky & Zheng, euchromatin. The heterochromatin is
2017). This approach aids in the creation of primarily composed of short, simple
diagnostic assays by offering a system to sequence repeats extending for many
evaluate the sensitivity and specificity of megabases, interspersed occasionally with
new diagnostic tools before they are used in transposable elements and tandem arrays of
humans. Furthermore, animal models enable ribosomal RNA genes. Drosophila has four
the long-term study of disease progression, pairs of chromosomes: X/Y, II, III, and IV,
which is often difficult to conduct in human with the majority of its genes located on
patients due to ethical and logistical chromosomes X, II, and III. The initial
constraints (Chamberlain & Chamberlain, annotated sequence, release 1, was published
2017). They are fundamental in the in March 2000 (Adams et al., 2000). The
development of assays for human diseases, haploid genome size is estimated to be 175
providing a platform to investigate disease Mb based on flow cytometry of propidium-
mechanisms, develop diagnostic tools, stained nuclei, a figure that closely matches
screen drugs, monitor disease progression, the 176 Mb reported in the release 3.2
and understand behavioral aspects of genome sequence. The number of protein-
diseases. coding genes, determined through in silico
gene prediction methods, is approximately
15,000, which is about half the number
Genomic profile
predicted in the human genome. Release 4.0,
which contained very few new annotations
The mitochondrial genome of
compared to release 3.2, was made public in
Drosophila shares common characteristics
April 2004. Release 5.0 of the genomic
with other animal mitochondrial DNA
sequences became available in 2006
(mtDNA) in terms of gene order, density,
(Fernández-Moreno et al., 2007).
and structure, and it uses a genetic code that
Since Thomas Hunt Morgan began
differs from the universal code. However,
studying Drosophila in 1910 it has been a
some genes are rearranged when compared
key genetic model organism. Its genome is
to the mammalian mitochondrial genome A
easily manipulated, and the small number of
notable difference is found in the noncoding
chromosomes makes gene mapping
region, which is composed of 90–96%
straightforward. Balancer chromosomes
deoxyadenylate and deoxythymidylate
have been developed to carry recessive
residues (the A+T-rich region) and varies in
lethal mutations through generations without
size from 1 to 5 kb among different
selection. The discovery of polytene
Drosophila subgroups. In D. melanogaster,
chromosomes in the salivary glands in the
the entire mtDNA molecule is 19,517 bp in
1930s provided a physical map for gene
length (Dowling & Wolf, 2023).
mapping. Genome-wide deficiency
collections help identify regions of haplo-
insufficiency and essential genes. Modern
techniques using engineered chromosomes,
such as two-element misexpression systems
like UAS/Gal-4, create gain-of-function Fasta sequence
phenotypes (Blazejewski et al., 2019). Site- >sp|P20480|NCD_DROME Protein claret
segregational OS=Drosophila
specific recombination can produce mitotic melanogaster OX=7227 GN=ncd PE=1
clones of entire chromosome arms or more SV=1
precise localized rearrangements (Germani MESRLPKPSGLKKPQMPIKTVLPTDRIRAGLGGGAA
GAGAFNVNANQTYCGNLLPPLSRD
et al., 2018; Urbano et al., 2018). LNNLPQVLERRGGGARAASPEPMKLGHRAKLRRSRS
ACDINELRGNKRTAAAPSLPSIPS
PROTEIN CLARET KVSRLGGALTVSSQRLVRPAAPSSITATAVKRPPVT
RPAPRAAGGAAAKKPAGTGAAASS
SEGREGATIONAL
GAAAAAPKRIAPYDFKARFHDLLEKHKVLKTKYEKQ
TEDMGELESMPQQLEETQNKLIET
ESSLKNTQSDNECLQRQVKQHTAKIETITSTLGRTK
EELSELQAIHEKVKTEHAALSTEV
VHLRQRTEELLRCNEQQAAELETCKEQLFQSNMERK
ELHNTVMDLRGNIRVFCRIRPPLE
SEENRMCCTWTYHDESTVELQSIDAQAKSKMGQQIF
SFDQVFHPLSSQSDIFEMVSPLIQ
SALDGYNICIFAYGQTGSGKTYTMDGVPESVGVIPR
TVDLLFDSIRGYRNLGWEYEIKAT
FLEIYNEVLYDLLSNEQKDMEIRMAKNNKNDIYVSN
ITEETVLDPNHLRHLMHTAKMNRA
TASTAGNERSSRSHAVTKLELIGRHAEKQEISVGSI
NLVDLAGSESPKTSTRMTETKNIN
RSLSELTNVILALLQKQDHIPYRNSKLTHLLMPSLG
GNSKTLMFINVSPFQDCFQESVKS
LRFAASVNSCKMTKAKRNRYLNNSVANSSTQSNNSG
SFDK

The claret segregational protein in

Drosophila melanogaster, encoded by the
ncd (non-claret disjunctional) gene, is
located on the X chromosome at the
cytogenetic position 3C6-3C7 (Wong &
Judd, 1977). The ncd (non-claret
Figure 1. Structure of protein claret disjunctional) gene encodes the claret
segregational in pymol software segregational protein, a motor protein
essential to both mitosis and meiosis in
Drosophila melanogaster. In order to ensure
that chromosomes are correctly aligned and
distributed to daughter cells during cell
division, this kinesin-like motor protein is
necessary for the proper segregation of
chromosomes. Through its interactions with
microtubules, Ncd helps to organize and diseases. Reverse genetics involves inducing
transport them, which is essential for the mutations in fly counterparts of human
formation of the mitotic and meiotic genes to observe their effects in vivo.
spindles. In Drosophila melanogaster, the Researchers employing this method, known
gene that codes for this protein is called ncd as "reverse geneticists," aim to deliberately
(non-claret disjunctional). The appropriate alter a gene or its expression and observe the
activity of the Ncd protein is essential for resulting phenotypic changes. With the
the normal course of cell division. Errors in advent of genome sequencing since the late
chromosomal segregation can result in 1990s, numerous genes with unknown
aneuploidy and developmental abnormalities functions have been identified. Assigning
in cells. The ncd gene can be mutated to functions to these genes involves various
produce aberrant chromosome segregation, approaches, including determining their
which can lead to disjunctional subcellular localization, identifying
abnormalities during mitosis and meiosis, associated molecular complexes, and
which can impair viability and fertility. Ncd, describing the phenotypes resulting from
a motor protein belonging to the kinesin-14 their manipulation. High-throughput reverse
family, travels toward the minus end of genetics techniques have thus become
microtubules as opposed to the plus end as pivotal tools in the post-genomic era (Hardy
do most kinesins. The ncd gene is frequently et al., 2010). There are primarily three
mutated, which can lead to phenotypic approaches to reduce or eliminate gene
problems include aberrant chromosomal expression in flies: targeted gene disruption
segregation, non-disjunction, various (Beumer & Carroll, 2014), transposon-
developmental disorders, and decreased mediated mutagenesis with subsequent
fertility. Numerous variants in the ncd gene transposable element (TE) excision, and
have been found through genetic gene silencing via methods such as RNA
investigations, shedding light on the gene's interference (RNAi) and CRISPR (Mohr,
crucial function in chromosomal segregation 2014). Beyond loss-of-function
and mobility during cell division. investigations, researchers can also
Chromosome segregation errors are introduce wild-type or mutant versions of
commonly observed in mutants, which can human disease-causing genes (transgenes)
result in discernible phenotypic alterations into flies to evaluate their effects in specific
and developmental problems (Fischer et al., tissues (Feany and Bender, 2000).
2023; Lin et al., 2014). In the context of forward genetics,
mutations are deliberately induced at
random, and subsequent screening of the
Strategies and assays utilized Drosophila
animals focuses on a specific phenotype.
for human disease
Forward genetic approaches, also known as
phenotype-based screens, entail inducing
There are three primary
mutations through chemical agents or
methodologies have emerged for
irradiation to randomly cause DNA damage.
investigating human diseases using fly
The resulting progeny of mutated organisms
models: reverse genetics, forward genetics,
are then subjected to phenotypic analysis to
and a novel diagnostic strategy aimed at
pinpoint abnormalities potentially arising
identifying genes implicated in human
from these induced mutations (Bucan, anatomical differences, both species employ
2013). Mutation induction can be achieved various neurons for information processing.
chemically or through transposon insertion For instance, Drosophila's visual system
techniques (Venken & Bellen, 2014). comprises approximately 115 neuron types,
Alternatively, mutants may be isolated by similar to vertebrates (Venken et al., 2011).
screening RNA interference (RNAi) While flies have significantly fewer neurons
libraries or collections of pre-existing overall, their simpler nervous system
deficiencies (Cook et al., 2012). This facilitates comprehensive gene and network
methodology is unbiased, allowing for the function assessments. Multiple assays,
identification of previously uncharacterized including those for hearing, flight, learning,
mutations within known disease genes and memory, offer insights into neuronal
(phenotypic expansion) and the discovery of function. Over the past two decades,
genes not previously associated with Drosophila has become a valuable model for
diseases. Therefore, forward genetics serves neurological disorders such as
as a potent means of uncovering novel genes neurodegeneration and epilepsy. Various
and understanding complex biological assays, like electroretinogram and
processes (Ugur et al., 2016). neuromuscular junction electrophysiology,
Lastly, the diagnostic strategy aid in studying these conditions, potentially
involves utilizing Drosophila to evaluate the informing therapeutic strategies (Simon and
pathogenic characteristics of rare variants Dickinson, 2010).
associated with human diseases. However, Additionally, twenty years ago, fly
this approach often proves insufficient for models of cardiovascular diseases emerged
identifying the causative gene variant when alongside the development of assays for
only three or fewer individuals are heart development and function (Ocorr et
examined. To address this limitation, we al., 2014). The Drosophila heart, known as
devised a pipeline that facilitates the precise the dorsal vessel, differs from the human
identification of the causative mutation. heart as it is an open circulatory system
Initially, the fly's homolog or ortholog is comprising a hollow, muscular tube closed
disrupted by integrating a GAL4 gene under at the posterior end. This vessel runs
the control of its native regulatory elements, longitudinally from the posterior abdomen
and subsequently, the resulting phenotype is into the thorax. Similar to the human heart,
evaluated. If the observed phenotype can be the fly heart is divided into four chambers
restored to normal by expressing the wild- separated by small valve-like openings
type UAS–human-cDNA but not by the through which hemolymph, the insect
human variant, the causative mutation is equivalent of blood, enters (Lehmacher et
confirmed (Bellen and Yamamoto, 2015; al., 2012). Each chamber comprises six
Wangler et al., 2015). Drosophila have great myocardial cells to facilitate hemolymph
contribution in the study of invertebrates. flow. The aorta, made up of minimally
contracting myocardial cells, transports
Like in nervous system assays in hemolymph to the head and then into the
Drosophila are essential for understanding body cavity. Molecular pathways governing
sensory processing, similar to humans, with fly heart development and function offer
shared genetic and cellular traits. Despite insights relevant to human heart physiology.
Mutations in its human homolog cause the human liver, recent studies reveal
congenital heart disease and sudden cardiac oenocytes to share more similarities with
arrest in middle age. Similarly, the hepatocytes, particularly in response to
identification of pannier (GATA4) and starvation. Oenocytes express numerous
Neuromancer (Tbx20) transcription factors homologs of human fat-metabolizing genes
in flies revealed a conserved cardiogenic and genes involved in hepatocyte
network, aiding studies of these factors in differentiation, including Hnf4-a and COUP-
human heart development (Ugur et al.2016). TF. Knockdown experiments targeting
The fly heart serves as a convenient model acetyl-coenzyme A-carboxylase (ACC), a
for studying invertebrate heart disease due to crucial enzyme in FA synthesis, specifically
conserved molecular pathways and a range in oenocytes lead to lethality, highlighting
of assays. In subsequent sections, we will their significance in FA synthesis. Recent
explore several cardiovascular assays and findings establish that both the fat body and
their mechanistic insights into human heart oenocytes in flies serve as functional
disease. Further information can be found in equivalents of the vertebrate liver (Ugur et
comprehensive reviews on the topic (Diop & al., 2016).
Bodmer, 2015).
Moreover, the human excretory
Liver disease is a significant cause of
system functions to eliminate metabolic
global mortality, with nonalcoholic fatty
waste and maintain ion balance. The
liver disease (NAFLD) being the most
nephron, comprising the glomerulus,
prevalent form in the USA alone, affecting
glomerular capsule, and renal tube, serves as
tens of millions of individuals annually
its basic structural and functional unit.
(Byass, 2014; Rinella & Sanyal, 2015).
Within the nephron, glomerular podocytes,
Given its widespread impact and associated
specialized epithelial cells surrounding
costs, understanding the underlying
capillaries in the glomerulus, play a crucial
mechanisms using model organisms is a
role in blood filtration to produce urine.
critical healthcare priority. In humans, the
They form a filtration barrier through
liver's metabolic functions, including
interdigitating processes separated by slit
detoxification, protein synthesis, and
diaphragms, facilitating blood filtration.
glucose regulation, are predominantly
Mutations in genes affecting this barrier can
carried out by specialized cells called
lead to kidney failure. Although
hepatocytes. During fasting, adipocytes
invertebrates lack nephrons, Drosophila
break down lipids into fatty acids (FAs) via
nephrocytes, particularly pericardial and
adipocyte triglyceride lipase (ATGL), which
garland nephrocytes, share striking
are then processed by hepatocytes.
similarities with podocytes. These
Prolonged fasting prompts hepatocytes to
nephrocytes, exhibiting extensive plasma
synthesize ketone bodies from FAs for
membrane folds and ∼30-nm slit pores,
energy (Green et al., 2015). Similarly,
form a nephrocyte diaphragm akin to the slit
during fasting, fly larvae release lipids from
diaphragm in mammalian podocytes.
their fat body, the primary energy storage
Functionally and molecularly, proteins
organ, which are absorbed by specialized
encoded by Drosophila homologs of
cells called oenocytes (Chatterjee et al.,
nephrosis 1 and nephrin 1 (NEPH1) interact
2014). Initially thought to be analogous to
across these slit pores in nephrocytes similar
to their mammalian counterparts. Apart from
nephrocytes, Malpighian tubules in flies
Drosophila as a Model Organism
serve to clear toxins, produce uric acid,
regulate ions, acid-base balance, and fluid Many of the pathways that regulate
equilibrium. Genes shared between flies and cell growth and invasion in mammals serve
mammals, such as vacuolar-type-ATPases similar functions in flies, making Drosophila
(V-ATPases), Na+/K+-ATPase, aquaporins, a valuable model for studying tumor
ion channels, and transporters, are involved biology. By combining genetic screens with
in maintaining ion homeostasis. Notably, advanced recombination techniques,
mutations in genes like rosy and maroon- researchers can quickly uncover the
like in flies result in sensitivity to dietary fundamental roles of oncogenes and tumor
purines and abnormal Malpighian tubules. suppressor genes within an entire organism.
The deficiency of rosy, encoding xanthine Recent investigations using Drosophila
oxidase, leads to type I xanthinuria in imaginal discs have delved into the
humans, as observed in fly mutants, where processes governing epithelial tumor
accumulation of xanthine, the substrate of growth, as well as their interplay with the
the rosy enzyme, occurs, elucidating the surrounding tumor microenvironment
disease mechanism. Additionally, (TME) and stromal cells. These studies have
Malpighian tubules have been employed to even begun to elucidate the mechanisms
model kidney stone formation, allowing behind immune cell recruitment, particularly
transparent observation of stone nucleation macrophages, to the tumor site (Mirzoyan et
and oxalate crystal growth in flies (Ugur et al., 2019).
al., 2016).
According to research by Piazza &
Important advances are made in our Wessells (2011), the fruit fly Drosophila
understanding of human physiology and melanogaster has emerged as a valuable tool
illness by using model species like for studying various aspects of cardiac
Drosophila. Research and novel therapeutic diseases, including both developmental
approaches can benefit greatly from the anomalies and functional impairments in
striking parallels between human and fly adults. By employing classical and
diseases, which include neurological molecular genetic methods, investigations
problems, cardiovascular ailments, and liver into the development of the fly heart have
conditions. Through the utilization of been pivotal in identifying key signaling
Drosophila's genetic versatility and common events involved in cardiac field formation,
molecular pathways, in conjunction with the cardiomyocyte specification, and the
advancement of sophisticated testing establishment of a functional heart tube.
techniques, we can further investigate the During the larval stage, the development of
mechanisms behind disease and investigate the fly heart has become a crucial model for
potential new therapeutic approaches. As evaluating the effects of biological and
such, using Drosophila as a model organism pharmacological compounds on cardiac
is a critical step in improving our activity using isolated preparations of living
understanding and addressing urgent hearts. Additionally, recent advancements in
healthcare issues. techniques for studying adult cardiac
function in flies have expanded the utility of levels of Aβ42 peptides specifically within
the Drosophila model. Researchers now the nervous system leads to observable
employ the fly system to examine prolonged characteristics indicative of neuronal
changes in adult cardiac performance degeneration, with the severity of these traits
induced by factors such as diet, exercise, and being contingent upon both the dosage of
natural aging. The Drosophila model stands Aβ42 and the age of the flies. Furthermore,
out as unique and valuable due to its they have identified a mutation in a
possession of a working heart that is Drosophila neprilysin gene, which mitigates
developmentally homologous to the the Aβ42-induced phenotypes by reducing
vertebrate heart, making it the sole the levels of the Aβ42 peptide. This
invertebrate genetic model system with this discovery lends support to the notion of
characteristic. Consequently, the fly model neprilysin's involvement in the breakdown
combines the advantages of invertebrate of Aβ peptides within a living organism.
genetics, such as large populations, easily Based on their results, Drosophila model
applicable molecular genetic techniques, and serves as a valuable platform for
a short lifespan, with physiological investigating and unraveling the intricacies
measurement methods that facilitate of Aβ metabolism and toxicity from a
meaningful comparisons with data obtained genetic perspective.
from vertebrate model systems. Therefore,
In recent discoveries regarding
the fly model holds significant promise for
intestinal pathology in Drosophila
shedding light on the intricate interplay
melanogaster, the study of Apidianakis &
between environmental factors and genetics
Rahme (2011) indicates that it is highly
in the long-term regulation of cardiac
suitable for investigating the physiology of
performance, thereby offering substantial
intestinal stem cells in the context of aging,
contributions to our understanding of these
stress, and infection. Despite the
complex interactions.
physiological disparities between vertebrates
In the study of Finelli et al. (2004), and insects, Drosophila can effectively
Alzheimer's disease, which a neurological model human intestinal diseases due to the
condition characterized by the deterioration significant conservation of signaling
and demise of brain neurons responsible for pathways regulating intestinal development,
memory, cognition, and behavior, poses regeneration, and disease between
significant challenges in understanding its Drosophila and mammals. Additionally, the
underlying mechanisms. While the excessive genetic tractability of Drosophila renders it a
production of Aβ peptides is widely particularly advantageous model species.
implicated as a contributing factor, the The extensively studied intestinal stem cell
precise pathways through which these lineage in Drosophila, coupled with the
peptides induce neurodegeneration, as well available tools for in vivo manipulation,
as the mechanisms involved in their offers a promising framework for exploring
clearance and degradation, remain elusive. various aspects of human intestinal
To tackle these unresolved questions, they pathology. In this Perspective, we delve into
have introduced the Aβ peptides into the recent advancements in understanding
genetic makeup of Drosophila melanogaster. Drosophila intestinal infection and
Our findings demonstrate that elevating the pathology while briefly comparing and
contrasting the processes of intestinal As the population ages,
regeneration and disease between humans neurodegenerative diseases impose
and Drosophila. significant challenges on families and
society at large. The intricacy of the brain
Moreover, Inflammatory bowel
and spinal cord, comprising a sophisticated
disease (IBD) is a persistent and potentially
network of neurons and supporting cells,
life-threatening inflammatory condition
underscores the complexity of these
affecting various segments of the human
conditions. One strategy to address such
intestine, presenting a global health
complexity is to investigate scientific
challenge with escalating incidence rates.
inquiries using simpler yet analogous
Due to its initially subtle symptoms, many
systems. Drosophila melanogaster, the fruit
cases go unnoticed, potentially leading to
fly, has emerged as a remarkably valuable
severe consequences. Urgent attention is
model organism, contributing significantly
required to develop novel therapeutics for
to major breakthroughs in the study of
halting disease progression. Natural products
neurological diseases. The extensive array of
offer a promising avenue due to their diverse
genetic tools available in Drosophila allows
active constituents, broad spectrum of
for precise manipulation of the genome
biological activities, and minimal toxicity or
((McGurk et al., 2015). It was assessed if
side effects, presenting new opportunities
Ref (2)P remains functionally intact during
for preventing and managing intestinal
the development of neural clusters. Nezis et
inflammatory disorders. Given its multiple
al. (2008) investigated Drosophila
genetic models, minimal ethical concerns,
melanogaster models of human
shared signaling pathways with mammals,
neurodegenerative disorders. They utilized
and low maintenance costs, the fruit fly
the pan-neural elav-Gal4 driver to express
Drosophila melanogaster has emerged as a
mutant human tau protein throughout the D.
suitable model for investigating the
melanogaster central nervous system.
mechanisms underlying IBD and devising
Examination via immunofluorescence
treatment strategies. This review of the study
microscopy of whole mount brains indicated
by Xiu et al. (2022), it highlights the
the presence of Ref (2)P-positive structures
advantages of using the fly model as a
in adult brains that coincided with tau. These
screening platform in drug discovery,
findings suggest that Ref (2)P can be
explores the molecular pathways conserved
involved in protein aggregates in D.
between mammals and flies that serve as
melanogaster models of human
therapeutic targets for IBD, assesses the
neurodegenerative disorders. The
feasibility of employing the Drosophila
aggregation of proteins is a prominent
model in IBD research, and summarizes the
characteristic in numerous
efficacy of natural products in IBD
neurodegenerative conditions, currently
treatment when evaluated using fly models.
being extensively researched for their
By providing a comprehensive analysis, this
underlying mechanisms. By employing the
review underscores the utility of flies as an
adult D. melanogaster brain as a model
ideal model for assessing the therapeutic
tissue, the study investigated protein
potential of phytochemicals against IBD.
aggregate formation and revealed that Ref
(2)P, analogous to mammalian p62, is a
significant constituent of these aggregates in variants of hGAT-1, all of which
the adult D. melanogaster brain. These significantly reduced or completely
aggregates form during natural aging, eliminated GABA uptake activity. Many of
coinciding with a decline in proteasomal and these variants disrupted normal cell surface
autophagic activities, likely contributing to localization due to protein misfolding and/or
the decreased mobility and eventual death of impaired trafficking machinery, as
older flies, as previously noted (Vernace et confirmed through confocal microscopy and
al., 2007; Simonsen et al., 2008). Ref (2)P de-glycosylation experiments. While a
also constitutes a major part of protein portion of the mutants correctly targeted the
aggregates in autophagy-deficient flies, plasma membrane, they still lacked GABA
those with impaired proteasomal function, transport function, possibly due to
and D. melanogaster models of human alterations in the GABA binding site or
neurodegenerative diseases. Crucially, both translocation pathway. They focus on the
the PB1 and UBA domains of Ref (2)P are folding-deficient A288V variant. In fruit
essential for protein aggregate formation, flies, A288V exhibited a pattern of impaired
suggesting that its capacity for expression reminiscent of ER-retention
multimerization and binding to ubiquitinated observed in transfected HEK293 cells.
proteins are vital functions during in vivo Functionally, A288V displayed a
protein aggregate formation. This claim was temperature-sensitive seizure phenotype in
supported also by the study of McGurk et al. flies. They utilized various small molecules
(2015) wherein they explore the attributes of to restore the expression and activity of
the fruit fly as a model for understanding folding-deficient hGAT-1 epilepsy variants,
human neurodegenerative diseases. Diverse both in vitro (in HEK293 cells) and in vivo
fly models representing various (in flies). Three compounds, acting as
neurodegenerative conditions exist, but their chemical and pharmacological chaperones,
focus lies on specific investigations exhibited moderate rescue efficacy for
concerning polyglutamine diseases and multiple variants. These findings provide
amyotrophic lateral sclerosis (ALS). These valuable insights into the molecular
selected studies showcase the depth and mechanisms underlying epilepsy in patients
breadth of insights attainable through fly with hGAT-1 mutations and demonstrate the
models. By delving into these models, they feasibility of correcting protein folding
emphasize the strengths of the fruit fly in deficits in disease-associated hGAT-1
elucidating underlying mechanisms and variants using pharmacochaperone
pathways, serving as a foundational platform approaches. Such innovative
for translational and therapeutic pharmacotherapeutic strategies hold
investigations. promises for designing novel drugs to
alleviate clinical symptoms caused by the
Moreover, mutations in the human γ-
increasing number of pathogenic mutations
aminobutyric acid (GABA) transporter 1
in hGAT-1.
(hGAT-1) can lead to myoclonic-atonic and
other generalized epilepsies in affected
individuals. In the study of Kasture et al.
Conclusions
(2023), they conducted a comprehensive
analysis of fifteen disease-associated
 The fruit fly, Drosophila Additionally, recent research on
melanogaster, has been used as a model human γ-aminobutyric acid transporter 1
organism to help us understand a number of (hGAT-1) mutations linked to epilepsy has
human diseases, such as epilepsies, heart shown the effectiveness of
ailments, neurological abnormalities, and pharmacochaperone approaches in restoring
neurodegenerative problems. Through the GABA transport function and correcting
use of Drosophila's genetic resources and deficiencies in protein folding, underscoring
physiological similarities, scientists have the possibility of creating novel medications
made significant strides toward to relieve clinical symptoms.
understanding the fundamental causes of
these disorders and investigating possible All things considered, the thorough
treatment approaches. When it comes to investigation of disease causes and
studying the fundamental roles of oncogenes therapeutic approaches utilizing Drosophila
and tumor suppressor genes within an entire models emphasizes how crucial it is to
organism, Drosophila has proven to be combine genetic, molecular, and
invaluable in the field of tumor biology. It physiological methods in order to effectively
has helped shed light on processes that treat the complexity of human diseases. The
govern the growth of epithelial tumors, their persistent progress in Drosophila research
interactions with the tumor bears potential for augmenting our
microenvironment, and the recruitment of comprehension of disease pathophysiology
immune cells to tumor sites. Similar to this, and expediting the creation of efficacious
studies on cardiac disorders have taken use remedies.
of Drosophila's developmental similarities to
vertebrate hearts, which have made it
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