The Journal of Quality Research in Dementia, Issue 1 (lay summary)

Using fruit flies to model human neurodegenerative diseases

Dr Amritpal Mudher

Lecturer in Neuroscience, School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton, SO16 7PX. Telephone 0238 059 4389; Fax 0238 059 4341; email a.mudher@soton.ac.uk

Fruit flies, milk bottles and porridge are all unlikely ingredients in a successful project that has significantly improved understanding of how neurofibrillary tangles affect nerve cells.

Amyloid plaques and neurofibrillary tangles are often referred to as the 'hallmarks' of Alzheimer's disease. They are both tiny but distinct structures that develop in the brains of people with the condition. Neurofibrillary tangles are also found in the brains of people with fronto-temporal dementia. They are flame-shaped structures that develop inside sick and dying nerve cells. The tangles' main component is a protein called tau, which is usually found in the longest part of nerve cells called the axon. Tau's normal function is to stabilise connection pipes, called microtubules, within the cell and to help form the cell's skeleton. The microtubules act as tracks for essential chemicals to be transported from one part of the cell to another. This axonal transportation system is how nerve cells communicate with each other.

Many researchers believe that when the tau inside nerve cells in the brain develops into tangles it cannot do its job properly, which in turn, when sufficient cells are affected, would explain some of the symptoms of Alzheimer's disease and fronto-temporal dementia, such as problems with memory or changes in behaviour. This is known as the 'tau and tangle hypothesis. But, as any good detective knows, circumstantial evidence on its own is far from satisfactory. What is needed is hard evidence of whether tangled tau proteins disrupt the transport of chemicals in a nerve cell axon.

Despite major advances in brain imaging techniques, we are not yet able to ascertain tau's role in brain nerve cells through straightforward observation. So the alternative is to develop a model of the axonal transportation system that can be closely observed.

Fruit flies

At first glance a fruit fly may seem an odd choice of organism in which to model a human disease. It is surely too simple to provide information that can be relevant to the far more complex human nervous system. In reality, it is its simplicity that makes it such an attractive choice - that and the surprising similarities that exist between fruit fly and human nerve cells.

More than 50 per cent of the genes implicated in human diseases have counterparts, called orthologs, in fruit flies. By tinkering with the genes in fruit flies and observing the outcomes, scientists can improve their understanding of what role those genes play in human biology and what happens when they have mutations. It is also possible to insert human genes into the fruit flies and then study the actions of that gene. This is known as a transgenic model.

Because fruit flies have been used in scientific research for many years, researchers have established a good working knowledge of their genetic system. Also, a number of tools have been developed that enable scientists to carry out what they like to term 'elegant research' (in this context the word elegant means 'beautifully simple'). For example, using a system known, somewhat inelegantly, as UAS-GAL4 enables researchers to place or activate any gene that they want to into any specific cell in the fruit fly. This level of control and accuracy is important when studying neurodegenerative diseases as often only specific nerve cells are affected.

The wide range of tools and tests that have been devised for experiments with fruit flies are able to quickly reveal which gene is doing what as well as identifying the other genes it interacts with, in an unbiased way. Researchers can screen the whole organism rather than having to limit their investigations to areas that they suspect are involved. It is also possible to use 'marker' genes to track inheritance of a gene through successive generations. In addition, fruit flies' short life span means it is possible to carry out life-long studies in a matter of weeks, rather than months, which would be the case with other animals such as mice or rats. Finally, as well as offering a range of ways that researchers can gain important insights into the mechanisms that underlie neurodegeneration, fruit flies are also very cheap to maintain as they live happily in milk bottle-style containers and eat a straightforward diet of porridge.

Testing the tau and tangle hypothesis

In 2001 the Alzheimer's Society funded Dr Amrit Mudher's testing of the tau and tangle hypothesis, using fruit flies. There had been previous attempts to test this hypothesis using individual cells in culture in the laboratory and also by using lab animals such as rodents, but none had been successful.

Dr Mudher bred fruit flies which made abnormal tau proteins and which also had glowing tags attached to the materials that were being transported in the axon. Because fruit fly maggots have transparent skins, it was possible to follow the movement of the tagged material in the nerve cell axons in real time.

The results showed that the 'tau and tangle' hypothesis is correct. In nerve cells with healthy tau, the fluorescently tagged cargo was swiftly transported along the motor neurone axons, but when any of the abnormal tau proteins were present, this transport became severely disrupted. In fact, most of the fluorescent cargo got caught in 'pile-ups' along the length of the axon and was not able to reach its destination - much like a severe traffic jam on a busy highway.

This disruption was evident even though the nerve cell was clearly still alive. As a result of this disruption the nerve cell was not able to communicate with other cells and behavioural abnormalities were clearly seen in the maggots and subsequently the flies' behaviour. For example, the maggots could not crawl well and the adult flies could not walk or fly properly.

Interestingly, when the maggots that had been bred to have abnormal tau were fed food containing lithium chloride, both the disruption of axonal transport and the behavioural defects disappeared. Lithium chloride was chosen because it acts on an enzyme known as GSK-3, which is known to change the properties of tau.

Establishing that nerve cells are still alive even though they are suffering from the disruption in axonal transport is a highly significant finding as it offers the prospect of being able to rescue the 'sick' cell before it goes beyond a point of no return. As the use of lithium chloride shows, the possibility of designing a drug treatment to reverse the damaging effects of neurofibrillary tangles on brain cells is now very real, thanks in no small part to several thousand fruit flies.

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