Project Title: Characterisation of axonal transport defects in mutant LRRK2-related Parkinson’s disease

Supervisors: Dr Alex Whitworth (BMS & CDBG) and Dr Kurt De Vos (Neuroscience & CMIAD)

Application deadline: Friday 14 December 2012.

Project Description:

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease and may also cause sporadic Parkinson’s disease. How mutations in LRRK2 cause Parkinson’s disease is not known.
Most axonal and synaptic components and organelles are synthesized in the cell body and transported into and through the axon to their site of action in a process called anterograde axonal transport. Signals originating at the synapse, and axonal proteins and organelles destined for autophagy are conveyed back to the cell body by retrograde axonal transport. The main mechanism to deliver axonal cargoes is microtubule-based fast axonal transport. Axonal transport is mediated by motor proteins that shuttle cargoes along the microtubules. Axons contain two types of microtubule-based molecular motors, kinesin and cytoplasmic dynein, which drive most anterograde and retrograde transport, respectively.

We now know that axonal transport malfunctions in a number of neurodegenerative diseases including Parkinson’s disease.  We also know that axonal transport malfunction is one of the earliest, and possibly the earliest defect in these diseases.  Therefore, understanding how healthy axonal transport works and what causes it to malfunction in these diseases is very important and is likely to reveal novel drug targets that may be developed into medicines aimed at sufferers from these diseases.

This project is part of our on-going research into the molecular mechanisms underlying neurodegenerative diseases and will focus on the role of axonal transport in Parkinson’s Disease-related neurodegeneration. We will investigate if mutations in LRRK2 disrupt axonal transport and determine the underlying molecular mechanism.

This research will involve mammalian and fly model systems and techniques such as advanced quantitative microscopy including time-lapse and confocal fluorescence microscopy of mitochondrial and vesicle dynamics and transport, siRNA technology, western blotting and recombinant DNA technology.

Contact Details:

Dr Alex Whitworth

Web: http://www.shef.ac.uk/bms/research/whitworth

Email: a.whitworth@sheffield.ac.uk

Dr Kurt De Vos

Web: http://sitran.dept.shef.ac.uk/DeVos.htm

Email: k.de_vos@sheffield.ac.uk