Leicester's fruit flies offer new hope for Huntington's disease

Posted by mjs76 at Jun 02, 2011 04:55 PM |
Groundbreaking research in our Department of Genetics has identified a crucial pathway – and a way to block it.
Leicester's fruit flies offer new hope for Huntington's disease

image: Wikipedia

Huntington’s disease (HD) is an incurable, inherited, neurodegenerative condition. Usually only becoming evident in later life, the condition is characterised by involuntary movements and memory loss as neurons in parts of the brain break down.

If we knew what caused this neurodegeneration, we could then set about finding a way to prevent or ameliorate it. New research from our Department of Genetics, published this month in Current Biology, heralds a major breakthrough. Dr Flaviano Giorgini and colleagues conducted experiments with fruit flies, Drosophila melanogaster, and demonstrated how an important element in HD neurodegeneration can be successfully inhibited.

In praise of fruit flies

Tryptophan is one of the ‘essential amino acids’ which cannot be produced by mammals and must be part of our diet. The metabolic pathway which breaks down tryptophan – known as the kynurenine pathway - contains three substances which can affect nerve cells, called KYNA (kynurenic acid), QUIN (quinolinic acid) and 3-HK (3-hydroxykynurenine).

Step forward our six-legged friend the fruit fly. This is a popular model for genetic studies: it has an extremely short life cycle; every bit of its genome is documented; and it shares a surprising amount of genetic information with Homo sapiens, including the kynurenine pathway. But Drosophila does not have quinolinic acid, meaning that we only have two antagonistic factors – 3-HK and KYNA - to consider when studying this pathway in flies, which makes things a lot simpler.

3-HK harms neurons by generating free radicals and KYNA protects neurons by scavenging free radicals. KYNA also counteracts excitotoxicity; that is, cell death in neurons caused by over-stimulation by neurotransmitters.

kynurenine pathway
The kynurenine pathway metabolises the essential amino acid tryptophan. Quinolinic acid is produced in simple organisms (eg. yeast) and higher organisms (eg. mammals) but not in Drosophila.

Fruit flies and their eyes

We can regulate this pathway using either of two proteins which catalyse different stages in kynurenine pathway metabolism: TDO (tryptophan-2,3-dioxygenase) or KMO (kynurenine 3-monooxygenase). And we can tell when one of these genes is mutated in a fly because the genes which encode them, called ‘vermillion’ and ‘cinnabar’, also control eye colour.

So although Drosophila are tiny, fiddly things, we can know their genotype by studying their phenotype: we simply knock them out with carbon dioxide, pop them under a microscope and check what colour eyes they have. (The kynurenine pathway also has an important role in mammalian eyes, helping to form ultraviolet filters in our lenses.)

How does this help us to study Huntington’s Disease?

HD and the fruit fly

Research into HD in other animal models has shown a correlation between the disease and alterations in the kynurenine pathway. Drosophila allow us to regulate that pathway and examine precisely how metabolites in the pathway modulate neurodegeneration.

The Leicester researchers found that flies expressing the HD gene (effectively, flies with Huntington's disease) had a significantly increased ratio of 3-HK to KYNA. But flies lacking KMO or TDO had a massively decreased ratio, ie. a lot less neurotoxic 3-HK and a lot more neuroprotective KYNA.

This was made evident by close examination of neurons in the animals’ eyes (photoreceptors called rhabdomeres). Flies lacking KMO or TDO showed much less degeneration of these photoreceptor neurons indicating a strong correlation between a decreased 3-HK/KYNA ratio and neuroprotection.

Comparison of Drosophila eyes
Normal 'wild-type' fruit flies (far left) have a cluster of seven photoreceptor neurons or 'rhabdomeres' in each of the 760 (x2) parts of their compound eyes. Flies expressing the HD gene (second left) have fewer rhadomeres, indicating neruodegeneration. Flies with HD plus either cinnabar (cn) or vermillion (v) retain most of their photoreceptors.

Chemical inhibitors

Having established a genetic basis for limiting the effects of HD in flies, the next question was whether this could be reproduced using an agent that inhibits the action of KMO. Three KMO inhibitors were tested and in all three tests the subjects demonstrated significant recovery of photoreceptor neurons.

However, testing one of the KMO inhibitors on flies that were already lacking the KMO gene did not confer additional neuroprotection, indicating that both gene and inhibitor were working in the same way.

The Leicester-San Francisco connection

This research provides solid evidence that the kynurenine pathway is intrinsic to HD neurodegeneration and that factors which inhibit KMO disrupt that pathway, thereby swinging the neurotoxin/neuroprotector ratio very much in favour of the latter.

A related paper is being published in Cell jointly with the publication of the Current Biology report. Led by Professor Paul Muchowski at the Gladstone Institutes in San Francisco (with contributions from Dr Giorgini), this study examined mouse models of both Alzheimer’s disease and HD. A KMO inhibitor called JM6 (one of the three used on the Leicester fruit flies) improved several symptoms in both of these mouse models, and also decreased neurodegeneration.

The Leicester research was funded by the Huntington’s Disease Association and the CHDI Foundation, Inc. The paper is dedicated to the memory of Dr Paolo Guidetti (1966-2007) whose groundbreaking research into this pathway laid the basis for the current work.

We are still a long way from a cure for either Huntington's disease or Alzheimer’s disease but we have taken a significant step towards understanding the processes leading to the damaged neurons that characterise these debilitating conditions.

Professor Giorgini explains how he and his colleagues use baker's yeast and fruit flies as model organisms: short version (2'57") or full version (9'11")

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