Role of microtubule acetylation in Parkinson's disease

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Nerve cells (neurones) transmit signals in the brain. They have a cell body and long string-like extensions (up to tens of inches) that connect to other neurones. These extensions are called axons. In Parkinson's disease the axons of neurones that produce a chemical called dopamine break down and connections are lost. This causes the neurones to die and as a result there is less dopamine in the brain. This shortage of dopamine in the brain causes the typical tremor, walking and talking problems associated with Parkinson's disease. The research in this project is to find out how neurones die in Parkinson's disease. We concentrate particularly on a process called "axonal transport". Axonal transport is like the Royal Mail's Parcel-Force but in neurones; it delivers all kinds of goods to their destinations in the axon. Technically axonal transport is like a train journey: Molecular motors ("the locomotives") hook up to cargoes ("the carriages"), and they ride on protein tracks called microtubules ("the rails") and use a "fuel" called ATP. When axonal transport breaks down the axon starves because no deliveries are being made, and eventually the neurone dies. Mutations in a gene called LRRK2 are the most common cause of familial Parkinson's disease (~7 in 100) and are also found in the sporadic, more common form of the disease (~3 in 100). We have found that mutant LRRK2 stops axonal transport of a cargo called mitochondria (which produce energy in the cell and are known to be involved in Parkinson's disease). Our investigations revealed that mutant LRRK2 most likely stops axonal transport by damaging the microtubule rails. Using this information we tested a number of drugs that act on microtubules and found one that was able to repair the defective axonal transport. This drug is called TSA (short for trichostatin-A). To test if this finding held up in a whole living organism we turned to a model of Parkinson's disease in fruit flies (Drosophila in Latin). These flies have the human disease causing LRRK2 mutations and have difficulties climbing and flying. So in their own way these flies have movement difficulties similar to those of human Parkinson's patients. We fed these flies TSA and we found that not only did TSA rescue the axonal transport defect but it also improved the movement problems of the flies. So, at least in the fruit fly a drug that modifies microtubules is working. However, flies are not humans and for this possible therapy to make it to the clinic more work is needed.In this project we want to investigate how TSA restores transport and why it protects neurones from dying. The most likely explanation is that TSA works by increasing a modification of microtubules called acetylation. Our first aim is to investigate if this is so. Secondly we don't know if the drug works on a specific LRRK2 related pathway or if it acts on an unrelated, but still beneficial, level. You can compare this with a painkiller such as paracetamol that relieves pain but doesn't cure the cause of the pain. We think that LRRK2 may act on proteins that regulate the acetylation of microtubules. This is what we want to investigate in our second aim. Finally, we want to find out if this novel mechanism is also involved in other forms of Parkinson's disease that are not caused by mutant LRRK2. This is important to establish the possible benefits of drugs that target microtubules as a therapy for all Parkinson's disease.In summary with this project we want to make significant inroads into understanding the reasons why neurones die in Parkinson's disease. We have already found a drug that may be beneficial and we now want to find out exactly how the drug does this. This is necessary to design the best therapeutic strategies and to try to avoid the disappointment of yet another failed clinical trial. If we are successful we will be one step closer to develop drugs such as TSA as a therapy for Parkinson's disease.