Promising new therapeutic strategy for Parkinson’s Disease

A new research project at SITraN investigates the potential of drugs that rescue axonal transport defects in Parkinson’s disease to keep nerve cells from dying.

Following on from their promising research published recently in Nature Communications, researchers Dr Kurt De Vos from SITraN and his collaborator Dr Alex Whitworth from the Department of Biomedical Sciences at the University of Sheffield have secured MRC funding to investigate a novel therapeutic approach in Parkinson’s disease.

The team hopes to make significant inroads into understanding the reasons why neurones die in Parkinson’s disease and how to counteract this. They have already found a drug that may be beneficial and now want to find out exactly how the drug does this in order to design the best therapeutic strategies.

One of the first things that can be seen in Parkinson’s disease is that dopamine producing nerve cells are dying. The resulting lack of dopamine in the brain causes the typical tremor, as well as the walking and talking problems associated with Parkinson’s disease. Dr Kurt De Vos and his team want to find out why and how these nerve cells die. They are particularly interested in investigating the role of a process called “axonal transport”. Axons are the string-like extensions of nerve cells through which they connect, transmit signals and communicate with other nerve cells in the brain. In Parkinson’s these axons, which can be up to ten inches long, break down, connections are lost and the nerve cell (neurone) dies.

 “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.” explains De Vos. “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.” 

The team has found that mutations in a gene called LRRK2, the most common cause of familial Parkinson’s*, stops the axonal transport of the energy producing mitochondria in the nerve cell. Their 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 we found one drug that was able to repair the defective axonal transport,” says De Vos. This drug is called TSA (short for trichostatin-A). We also tested if this finding held up in a whole living organism using a model of Parkinson’s disease in fruit flies (Drosophila in Latin).”

Following on from these positive results (see our news story here), the team will now investigate how this drug restores transport and why it protects neurones from dying. According to their studies so far, 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”, says De Vos. “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. 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. Notably, patients with these mutations present with Parkinson’s that is not clinically distinguishable from other Parkinson’s disease. So we hope that by studying mutations in LRRK2, we can learn something about all Parkinson’s, not just the rare mutant LRRK2 cases. If we are successful, we will be one step closer to develop drugs such as TSA as a therapy for Parkinson’s disease.”

*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).