[Research Grant] Role of microtubule acetylation in Parkinson's disease
Ente: Medical Research Council
Scadenza: 2018-09-27
Paese: GB
Descrizione
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 th
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD). LRRK2 is a multifunctional protein comprising GTPase and kinase activities that affects many cellular processes. How mutations in LRRK2 cause PD is not known.
We have found that pathogenic mutations in the LRRK2 Ras of complex proteins (Roc) GTPase domain (R1441C) and the carboxy-terminal of Roc (COR) domain (Y1699C) domain preferentially associate with deacetylated microtubules, and inhibit axonal transport in vitro in primary neurones and in vivo in transgenic Drosophila larvae. Moreover these LRRK2 Roc-COR domain mutants caused locomotor deficits in vivo in adult transgenic Drosophila. Treating neurones with the histone deacetylase inhibitor Trichostatin A (TSA) to increase microtubule acetylation restored axonal transport in vitro and systemic administration of TSA to transgenic mutant LRRK2 flies was able to restore axonal transport in vivo. Furthermore post hoc administration of TSA reversed the locomotor deficits in adult LRRK2 Roc-COR mutant transgenic flies. Thus, our findings reveal a novel pathogenic mechanism for mutant LRRK2 and a potential therapeutic intervention for PD.
In this project we will test the hypothesis that disruption of MT acetylation by mutant LRRK2 is a neurotoxic event in PD that leads to neuron death by disrupting axonal transport.
Our aims are to investigate:
(1) the therapeutic potential of MT acetylation and the (de)ace
Settori: Neurosciences
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.