School of Biological and Chemical Sciences

Protein Misfolding and the Molecular Basis of Alzheimer’s Disease

Supervisor: Dr John Viles

Project description

Worldwide one in three people over the age of 65 will die with Alzheimer’s Disease (AD). The disease is characterised by deposits of amyloid plaques and fibrils of amyloid-beta peptide (Ab) are their main constituent. The early stages of the amyloid cascade are characterised by the self-association of Ab peptide into toxic oligomers and protofibrils, which then convert to mature amyloid fibers. Although the link between amyloid-beta peptide and Alzheimer’s disease is clear, the nature of the toxic form of Ab and the mechanism of toxicity is not well understood. The cellular prion protein and copper ions have been linked with AD-phenotype in animal models (Laurel et al Nature 2009, You et al PNAS 2012). We hypothesise that the cellular prion protein and copper ions can profoundly influence this protein misfolding pathway; trapping and promoting Ab in a toxic oligomeric form that disrupts synaptic function, (Viles, FASEB 2013, Viles, JBC 2010). 

We want to further characterise the structure, interaction and nature of the prion protein and copper trapped oligomeric Ab complexes. In particular, we want to probe the toxicity and toxic mechanism of these trapped Ab oligomers at the synapse. 

Facilities and training

The PhD student will use and gain expertize in a range of biophysical and spectroscopic techniques (NMR, TEM, AFM, Florescence, IR, CD and EPR in the Viles lab) to probe the structure of the Ab/prion-protein and Cu/Ab complexes. The neurotoxic action of these isolated trapped oligomers will be studied using a range of approaches, including; (i) A vesicle model of membrane permeability (ii) Measurements of synaptic health (iii) Toxicity in Drosophila models (iv) Cell viability. 

Queen Mary University of London has recently joined the Russell group and is one of leading research focused institutions in the UK. The successful applicant will enter a vibrant research environment, under the supervision of Dr John H Viles. Currently (2014) Dr Viles' lab has four PhD students and a Wellcome-Trust postdoc, who have considerable expertise between them.

The lab is well equipped to carry out all the biophysical measurements outlined (> a million pounds of external funding in the past ten years) with world class TEM, AFM, NMR, and EPR facilities. With an outstanding track record in PhD student supervision. All past PhD student have submitted in four years and have generated high impact first author publications.

Dr John H. Viles is an Associated Professor in Biochemistry.

See also