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Introduction
In the late 1800s and early 1900s,
psychologists began to formalize the process
of learning and memory in laboratory
experiments. In this context, learning
is defined as a durable modification in
behavior due to a prior experience.1,2
The perseverance of these behavioral
responses over the time is known as
memory. Memories can last for various
lengths of time, which can be categorized
into two main types short-lived and long-
lived. Behavioral plasticity, which results
in memory formation, is of one of the
essential biological processes involved in
fitness and survival of an organism. Study
of behavioral plasticity is largely faced with
the complexity of the neural circuits and
behavioral responses.
Pavlov3 formally distinguished two types
of learning in the laboratory. One form
was called non-associative learning, that
could be either sensitization (an elevation
in behavioral response due to encountering
a single stimulus), or habituation (a decline
in a behavioral response following exposure
to a single stimulus). Another form of
learning was called associative learning.
That referred to a change in the behavioral
responses due to a temporal association
of two stimuli in time.4 There are two
basic types of associative learning. One is
operant conditioning, which means that an
animal is rewarded or reinforced for doing
something in response to the stimulus. If
the animal does not do the right response
to the stimulus, it is not rewarded or it is
punished. Another type of associative
learning is classical conditioning or
Pavlovian conditioning that includes a
temporal association of 2 stimuli in time
regardless of what the animal does in
response to the stimuli.5
Several mammalian model systems have
been employed to study the behavioral
plasticity and age-related senescence in
doi 10.15171/ijbsm.2018.02
Drosophila melanogaster as a Model to Study
Human Neurodegenerative Diseases
Mohammad Haddadi*
Department of Biology, Faculty of Science, University of Zabol, Zabol, Iran
Abstract
The central nervous system (CNS) is the most complex part of the human body, which controls
a variety of cellular and molecular activities. Neurobehavioral functions of CNS play a vital role
in making appropriate responses to the environmental stimuli. Some kind of such responses
can be maintained in neural networks due to neuronal plasticity. When brain ages, or being
damaged by means of genetic or environmental factors, memories will disappear gradually.
Molecular mechanism of memory formation and disruption are studied during normal and
diseased conditions, respectively. However, it is far to understand the complete scenario and
we need a model organism to undertake specific studies and unravel the mystery of neuronal
function. The fruit fly, Drosophila melanogaster possesses many characteristics, which enable
neuroscientists to model wide range of complex behaviors and find their neural circuit. Even
though, many human neurodegenerative disorders (NDDs) can be modeled in this insect and
provide unique opportunities for effective therapeutic interventions. Here I summarized few
points on the contribution of D. melanogaster in the neurobiology of learning and memory as
well as human NDDs.
Keywords: Drosophila melanogaster, Learning, Memory, Neurodegenerative Diseases
*Correspondence to
Mohammad Haddadi,
Email: m.haddadi@uoz.ac.ir
Received December 17, 2017
Accepted January 5, 2018
Published online March 31, 2018
Int J Basic Sci Med. 2018;3(1):9-12 Mini-Review
http://ijbsm.zbmu.ac.ir/
© 2018 The Author(s); Published by Zabol University of Medical Sciences. This is an open-access article distributed under the terms of
the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Please cite this article
as follows: Haddadi
M. Drosophila
melanogaster as a
model to study human
neurodegenerative
diseases. Int J Basic
Sci Med. 2018;3(1):9-
12. doi:10.15171/
ijbms.2018.02.
Haddadi
International Journal of Basic Science in Medicine. Volume 3, Issue 1, 2018
10
neural function. In addition to a longer lifespan, their
complex behavior machinery is not easy to measure, as it
comprises engagement of highly entwined brain circuits.
Therefore, a simple model organism is advantageous to
study the mechanisms underlying memory formation and
behavioral plasticity and neurodegeneration processes.
Drosophila melanogaster as a Model for Neurodegenerative
Diseases
For more than ten decades since William Castle at Harvard
University introduced Drosophila melanogaster as a model
system, it has been used in laboratories for a wide variety of
studies including genetics, cell biology, electrophysiology,
and behavioral genetics. D. melanogaster is a harmless
insect with small size, relatively short life cycle of 10-12
days at 25°C, which makes it possible to investigate a large
number of animals sharing a similar genetic background.
Therefore, behavioral phenotypes can be correlated with
manipulations under test.
Drosophila melanogaster is a powerful model system
for investigating the biology of neurodegeneration.
D. melanogaster shares many functions with humans
rendering this as a suitable model for studying human
diseases. D. melanogaster is an extremely obedient
genetic model for divulging the molecular basis of
human diseases. In fact, there are numerous biological
functions preserved between this fly and mammals.
Something like 75% of human disease-causing genes
have a functional homolog in D. melanogaster.6 Fruit fly
shows a variety of well-known behavioral responses like
positive phototaxis, negative geotaxis, and courtship and
mating. They are able to associate between certain cues
of their habitat environment and establish a memory. On
the other hand, rich repertoires of experimental methods
have strengthened the experimental benefits of using
Drosophila in order to dissect out the molecular players
and cellular pathways involved in associative memory.
One of the very well established kinds of memory in
Drosophila is olfactory conditioning associative memory.
There is a number of reasons illustrating that olfactory
memory is a subject for studying the neurological features
of learning and formation of memories in general. There
is a remarkable similarity between the structure and
function of the olfactory neural system among different
types of animals, especially insects and mammals. Thereby,
the principles and findings established in studying a
model organism can easily be extended to the others. On
the other hand, some sensory neural systems (for example
visual or somatosensory systems) show less similarity
index between different species. Olfactory memory
function could also be the subject of neurological studies,
as many of model organisms own a keen olfactory system.
Amazingly, Drosophila is enabled to comprehend a precise
3D picture of its environment through its compound eyes
and skillful olfactory and learning functions. Moreover,
olfactory memories are believed to be special in their own
right. Odors can mediate immediate alteration in affective
states and arousal level; produce a tremendously precise
memory of associated emotional experiences, which can
persist for decades. Classical olfactory conditioning is a
well-established conditioning paradigm in Drosophila,
which studies the capacity of flies to associate between
olfactory stimulus and an aversive mechanosensory input.
Quinn and Benzer7 in 1974 were the first to demonstrate
that flies can learn to avoid the odor, which was presented
earlier in association with electric shocks. Later on, this
model was improved by Tully and Quinn8 by setting up
critical training and testing parameters that have been
extensively adopted by many researchers to date.
The GAL4/UAS System
A GAL4/UAS system is a genetic tool in flies that makes it
possible to express transgenes in tissue-specific patterns.
GAL4 is a transcription factor in yeast that can bind
to upstream activating sequence (UAS) and activate
the transcription process. The GAL4/UAS system in
Drosophila works in the same manner as in the yeast. Two
individual transgenic lines, one for control of expression
and the other one for transcription of the selected gene,
can be constructed, separately. This binary system offers
a generation of two separate stock libraries, one library
for GAL4 stocks and a separate library for UAS stocks.
Direct cloning of the GAL4 gene under promoters and
enhancers of specific tissues is another powerful approach
called as enhancer detection used in the generation
of Drosophila library with distinct GAL4 expression
patterns9. Every GAL4 stock is referred to a driver
and several drivers have been constructed by random
insertion of the GAL4 containing transposable P-element
in the Drosophila genome. Following insertion, the
flanking regulatory elements, enhancers, and promoters
induce the tissue-specific expression of GAL4 in each
individual driver, which subsequently can bind to UAS
and activate expression of the gene of choice in a spatially
restricted manner. Therefore, by making a genetic cross
between any of tissue-specific, GAL4 stocks and a UAS
stock containing the selected gene; its tissue-specific
expression will occur. Since GAL4 and UAS components
are exogenous, there is no endogenous element for
binding of GAL4. Therefore, the GAL4/UAS system
will not induce non-specific expression of endogenous
genes or the target gene in Drosophila. In addition, GAL4
over-expression seems to have no significant phenotypic
effect in Drosophila. The main advantage of the GAL4/
UAS system is the independence of expression control
and activation of transcription.9 By making use of GAL4/
UAS, a number of Drosophila transgenic lines have been
generated resembling human disorders.10-12
Neurodegenerative disorders (NDDs) are main
conditions that lead to a remarkable mortality among
elderly populations throughout the world. Although the
majority of NDDs are sporadic, a ratio of 5%–10% have
International Journal of Basic Science in Medicine. Volume 3, Issue 1, 2018 11
Haddadi
been estimated to be hereditary.13 In this connection, there
are very well-known mutations in synuclein alpha (SNCA)
gene to cause autosomal dominant Parkinsonism.14
Likewise, mutations in microtubule associated protein
tau (MAPT) gene can develop frontotemporal dementia
with pakinsonism (FTDP) via formation of neuronal Tau
tangles.15 To combat the pathogenic events occurring in
neurons, we need to unravel the mechanism of action of
genetic factors that play key roles in these diseases.
Many human NDD can be studied using the fruit
fly, D. melanogaster. This is because large numbers of
disease-causing genes share a homolog in D. melanogaster
genome.16 However, there are some disorders that
their counterpart genes have not been identified in any
incest. By the help of Gal4/UAS genetic tool, we have
demonstrated that overexpression of human genes of
interest in Drosophila neurons exerted neurotoxicity
providing an opportunity to scrutinize genes involved
in these pathways and to address few therapeutic
interventions.
Overexpression of mutated human alpha-synuclein
in Drosophila exhibits symptoms that are found in PD
patients including locomotion defects.14,17 The transgenic
Drosophila models expressing MAPT have shown
premature death accompanied by cognitive dysfunction.18
We also created the first transgenic fly model of a NDD by
expressing ε3 and ε4 isoforms of human apolipoprotein
E (ApoE).19 ApoE4 is the strongest known genetic
risk factor for Alzheimer’s disease development so far.
The constructed genetic model exhibited progressive
neurodegeneration, shortened lifespan, and memory
dysfunction. Considering the mystery underlies APOE-
mediated neurodegeneration, Drosophila model may
facilitate analysis of the molecular and cellular events
implicated in human ApoE4 neurotoxicity.
Drosophila Model to Environmental Toxin-Induced
Neurodegenerations
Besides genetic factors, many environmental stimuli are
able to develop neurodegenerative conditions in human
beings. Most of these factors include toxic and chemical
agents such as insecticides, herbicides, and ethanol
and so on. Almost all these agents promote an excess
generation of free radicals, imbalance oxidative status of
cells imposing sensitive tissues an oxidative stress (OS)
condition. OS is involved in a wide range of disorders
including NDDs.13 Although there are well-characterized
mechanisms explain OS-mediated cell damages, the
complete scenario remains to be elucidated.20 The fruit fly
can be a suitable in vivo model organism for this type of
researches. We could model parkinsonism in flies through
chemical neurotoxins like paraquat and ethanol and
show in part, how they can induce neurodegeneration21.
Moreover, both the genetic and environmental factors can
be possibly combined in Drosophila to investigate possible
gene-environment interactions that might be involved in
neuronal disease condition.22,23
Current Facilities and Future Perspectives
Advanced fly research laboratories are set up in Iran in
very recent years. Department of Biology, University
of Zabol and Genetic Research Center of University of
Social Welfare and Rehabilitation Sciences have initiated
research activities focused on familial intellectual
disability (ID). ID is considered as a multi-factorial
disorder with a high prevalence that imposes remarkable
social and cost burdens on society. During an extensive
case-control study in Iran, a number of novel genetic
mutations have been identified which are associated
with the disorder. Although these genetic factors can be
undertaken as diagnostic markers, their functional role
needs to be vetted to propose better-aimed therapeutic
interventions.
In this connection, a small fly lab has been established in
the center. The specific aims of this action are to evaluate
functional role of novel genetic variations associated with
human intellectual disability in an in vivo model system,
to introduce the mechanism of actions through which
these mutations deregulate human brain function and
result in intellectual disability, and propose a novel genetic
interaction network involved in human ID. The final goal
is assisting in the establishment of more efficient medical
considerations for ID treatment.
These kind of studies can be expanded and target
more features of molecular defects underlying ID. This
objective can be achieved by including more genes and
other elaborated neurobehavioral analyses. Once relevant
genes that lead to the disorder are identified and fly
models are generated, drug screens can be performed in
the future to identify drugs that will ultimately help the
patients.
Conclusion
Taken all together, it is to be concluded that fruit fly, a
tiny model organism, can be used to explore molecular
mechanisms behind many genetic variations leading
to human genetic disorders. This is not restricted to
NDDs, rather could cover a wide spectrum of diseases
such as retinal degeneration, muscular dystrophies,
cardiovascular malfunctions, metabolic disorders and
so on. There is a huge number of published studies on
fly models of human diseases in the past 30 years, which
serves a major contribution to the medical society for
developing diagnostic and therapeutic inventions. Now, it
is crucial to establish more fly labs in our medical research
centers.
Ethical Approval
Not applicable.
Competing Interests
The author declares no conflict of interest.
Haddadi
International Journal of Basic Science in Medicine. Volume 3, Issue 1, 2018
12
Acknowledgments
I would like to thank Chairperson of Biology Department,
the University of Zabol for all help and supports.
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