Common Fruit Fly or Vinegar Fly under microscope (Image: Getty)
UK scientists claim fruit flies could hold the secrets to beating cruel health conditions that have baffled medics for decades – including Alzheimer’s, Parkinson’s and motor neurone disease. Scientists have long known that these and other neurodegenerative disorders can be traced back to genetic mutations, but how they cause the diseases remains unanswered.
Now – in the journal Current Biology – the University of Manchester’s Professor Andreas Prokop revealed that so-called ‘motor proteins’ can provide key answers in this quest, after studying them in fruit flies, insects that boast similar gene behaviour to humans. Research has focussed on nerve fibres called axons – delicate ‘cables’ sending messages between the brain and the body to control our movements and behaviour – and which need motor proteins to stay active, which can crucially be prone to mutations stopping them working.
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Professor Prokop said: « So far, it has been difficult to explain why both disabling and hyperactivating mutations can cause very similar forms of neurodegeneration.
« To find answers, we use fruit flies, where research is fast and cost-effective and where many of the relevant human genes have close equivalents and perform similar functions in nerve cells.
« Capitalising on these advantages, we could show that disabling as well as hyperactivating mutations cause a very similar pathology in axons: straight microtubule bundles decay into areas of disorganised microtubule curling, similar to dry versus boiled spaghetti. »
To survive long-term, axons harbour complex cellular machinery. This machinery crucially depends on the transport of materials from the distant nerve cell bodies which is performed by motor proteins running along thin fibres called microtubules.
The University of Manchester scientist explained: « If mutations in motor protein genes abolish their ability to transport cargo, this causes axonal decay, and many inherited neurodegenerative diseases can be traced back to such mutations.
« However, another class of mutations also linking to neurodegeneration, causes motor protein hyperactivation – meaning that motor proteins are constantly active, unable to pause.
« Further investigations revealed that hyperactivating and disabling mutations work through two different mechanisms that eventually converge to induce this ‘microtubule curling’.
« Even under normal conditions, cargo transport along microtubules generates damage, like cars cause potholes – and this requires maintenance mechanisms to repair and replace microtubules.
« The balance between damage and repair is disturbed if motor proteins are hyperactivated or if maintenance machinery fails – both leading to microtubule curling as a sign of axon decay. »
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Prof Prokop added: « In this scenario, disabling mutations could be assumed to cause less curling because there is less damaging traffic.
« However, less traffic depletes supply to the axonal machinery, and this triggers a condition referred to as ‘oxidative stress’.
« We could show that oxidative stress affects microtubule maintenance and leads therefore to the same kind of microtubule curling as observed upon motor hyperactivation.
« These findings suggest a circular relationship which we called the ‘dependency cycle of axon homeostasis’, proposing that axon maintenance requires a microtubule- and motor protein-based machinery of transport which, itself, is dependent on this transport. »
Any gene mutations affecting axonal machinery in ways that cause oxidative stress, or that disturb the balance between microtubule damage or repair, can break this cycle.
This can explain a long-standing conundrum in the field: why almost any class of neurodegenerative disease can be caused by mutations in a wide range of genes linking to very different cellular functions.
He added: « Parallel work by my group strongly supports the dependency cycle model.
« Importantly, since the fundamental genetic makeup of fruit flies and humans is surprisingly similar, it is very likely that our findings are replicated in humans – and there are good indications already. »
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