The suprastructure-function relationship between amyloid assemblies and their toxic and infectious potentials

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

This project will discover and quantify the structure-function relationship of amyloid aggregates in nanometre to micrometre range and address a long-standing question of why some amyloid are disease associated while others are tolerated by cells. We will test our hypothesis that, whether amyloid aggregates elicit toxicity and/or whether they are able to propagate as prions or prion-like particles, is determined by their structures in the mesoscopic length scales. We will systematically visualise suprastructure formation in aggregated samples of short amyloidogenic penta/hexa-peptide sequences, human amyloid-beta peptides, human alpha-synuclein, and yeast Sup35NM prion protein using force-curve based AFM imaging, combined with complementary methods including TEM and dynamic light scattering. From the resulting imaging and biophysical data sets, we will enumerate suprastructural parameters (e.g. distributions of length, width, morphology, twist, clustering, persistence length, deformation, modulus etc.) for each of the amyloid. In parallel, we will also perform a range of cellular assays to measure the effect of the same set of amyloid samples on cell viability (e.g. live-dead, internalisation, intracellular accumulation, transmission etc.). Finally, we will combine the structural and the biological/cellular parameters and perform principle component analysis, partial least squares analyses, and agglomerative hierarchical clustering (unsupervised machine-learning method) to discover hidden patterns and links in, and between, key structural parameters and key biological/cellular effects, and to show which and how much the suprastructural parameters are key biological determinants for amyloid aggregates. To further test the predictive power of our hypothesis, we will also find conditions that systematically trap different suprastructures and test their biological response in comparison to our model.

The results that will emerge from this project will be of significance to researchers working in the biomedical sector (both academic and industrial) with an interest in protein misfolding disorders such as Alzheimer's disease and Parkinson's disease. The information that we expect to provide through our studies will inform strategies aimed at developing novel therapeutic strategies by informing potential effective targets. Amyloid diseases are of increasing medical and social importance, for example, more than half million people are suffering from AD in the UK alone, and PD affects about 1% of the population over the age of 60. Therefore, in the longer term this has the potential of having profound benefits to human health and the UK economy since the costs of caring for individuals suffering from dementias is already in the £billions annually and will continue to rise as does the numbers of cases of dementia associated with protein misfolding disorders. It is currently estimated that in the western world, if an individual reaches the age of 85, they will have a 1 in 4 chance of developing Alzheimer's disease. With the average lifespan of humans in the UK already 82 years for women and 78 years for men, the emerging crisis we face is evident. The amyloid diseases also have adverse impact beyond the affected individuals themselves including carers and dependent family members. Improvements in the post-symptomatic treatment or pre-symptomatic prevention of such disorders thus have high potential for positive impact felt in wider society in the longer term.