Neurodegeneration:Drosophila as a Model for Human Disorders
The fruit fly brain is complex and contains subpopulations of neurons (specialized cells of the nervous system that convey information through electrical and chemical signals) that share anatomical and molecular similarities to humans. For example, the neurotransmitters (chemical messengers of the nervous system) of flies are related to those of humans. Like us, flies use their nervous system to direct locomotion and behavior. Therefore, the study of the Drosophila brain can reveal how our brains function, both in healthy and diseased states. To learn more about the Drosophila brain, explore Flybrain: An Online Atlas and Database of the Drosophila Nervous System.
Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, affect more than 100 million people worldwide. These diseases result in the progressive loss of specific neurons, often causing severe neurological dysfunction and sometimes death. Surprisingly, most neurodegenerative diseases are associated with the formation of protein aggregates (large clusters of a specific protein) that form either within or outside of neuronal cells.
As mentioned above, the fly brain comprises molecules related to those of humans, including the toxic proteins that aggregate in the brain during the neurodegenerative disease process. To produce a fly model that mimics a human neurodegenerative disorder, two approaches can be taken. If the fly has a related gene (homolog) implicated in causing a human neurodegenerative disease, the corresponding gene can be mutated within the fly to see if similar neurological symptoms are observed. Alternatively, a human gene associated with the neuronal disease can be introduced into Drosophila by genetic engineering in an attempt to mimic the human disease state.
Using Flies as a Model for Alzheimer's Disease
Alzheimer's disease, the most common cause of dementia in humans, is associated with the formation of neuronal aggregates containing amyloid β and tau proteins. Flies that are genetically engineered to overproduce amyloid β and tau proteins exhibit symptoms similar to Alzheimer's disease in humans. In fly eyes, the over-production of human tau protein causes the eye to appear rough, which can be easily visualized under the microscope.
- Understanding Alzheimer's Disease with Fruit Flies
- Learning to Fly: Fruit Flies, Aging, and Dimentia
Using Flies as a Model for Parkinson's Disease
In humans, Parkinson's disease is associated with the progressive loss of cells that secrete the neurotransmitter dopamine. A hallmark of this disease is the formation of neuronal protein aggregates comprised of the protein α-synuclein that are thought to lead to cell death. Following introduction of the α-synuclein gene into the fly genome by genetic engineering, a fly model for Parkinson's was created. These flies form aggregates of α-synuclein protein, display the progressive loss of neurons that secrete dopamine, and show some of the symptoms of human Parkinson's disease.
Using Flies as a Model for Huntington's Disease
Huntington's disease (HD) in humans is caused by a genetic mutation in which a repeating unit of three base pairs (called a trinucleotide repeat) is expanded in the gene encoding the huntingtin protein. When the mutated gene is translated, the protein contains additional glutamine amino acid residues that cause the huntingtin protein, along with other cellular proteins, to aggregate. Flies genetically engineered to express this mutant human huntingtin protein display some of the symptoms of human Huntington's disease.
- What other neurodegenerative disorders can you think of?
- Are all of these disorders heritable (passed on generation to generation)?
- Provide a hypothesis for what cellular processes could be hindered by large protein aggregates within neurons.
- How could scientists use these models to study potential disease therapies? Propose an experiment to accomplish this goal.