Neurodegeneration

Alzheimer’s and Parkinson’s disease are chronic, long-lasting, and so far, incurable neurodegenerative diseases. There are over 800,000 people living with dementia in the UK today, and this number is expected to rise rapidly as the population ages. Alzheimer’s disease is the most common cause of dementia, and according to figures published by the Alzheimer’s research trust, dementia costs the UK £23 billion per year, the vast majority of which is spent on care, rather than research.

The pathological hallmark of these diseases is the presence of insoluble protein deposits in the brain, which are formed when specific protein molecules mis-fold and aggregate (clump together) into highly ordered fibrils. In Alzheimer’s disease, the deposits are primarily made up of amyloid-beta, whereas in Parkinson’s, the major protein is alpha-synuclein. Rather than the fibrils themselves being toxic, much evidence now points towards the smaller, soluble oligomers formed in the initial stages of the process, as being the culprit. It is vitally important to characterise these oligomers and determine how they are formed, and more importantly, how they damage neurons.

During the aggregation process, the total concentration of oligomer may be much less than 1% of the total protein concentration. Therefore, in order to look at the oligomers, single molecule techniques must be used. Our methodology involves labelling half a population of the protein of interest (either alpha-synuclein, or amyloid-beta) with one colour, and the other half with another colour, and then observing the solution as the protein aggregates (within a test-tube). At the start, there will mainly be monomer and so each species will have only one colour dye. However, over time, the monomers will clump together to form oligomers, and so the species will be likely to have more than one colour. By looking at the progression of only the two-coloured species over time, it is possible to follow the oligomer formation process. The size/structure of the oligomers can also be determined by looking at the intensities of them. The conditions of the experiment can then be changed (i.e. by adding potential drugs, changing the biological environment etc.) and the effect on the aggregation observed.

Team members

Zoe Gidden

Owen Kantelberg

Craig Leighton

Beccy Saleeb

Ji-Eun Lee

Noelia Pelegrina-Hidalgo

Alex Chappard

Eleanor Mathias

Bhanu Singh

Zuzanna Konieczna

Selected Recent Publications

Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation

Angelova, P.R., Choi, M-L., Berezhnov, A.V., Horrocks, M.H., Hughes, C.D., De, S., Rodrigues, M., Yapom, R., Little, D., Dolt, K.S., Kunath, T., Devine, M.J., Gissen, P., Shchepinov, M.S., Sylantyev, S., Pavlov, E.V., Klenerman, D., Abramov, A.Y., Gandhi, S.

Cell Death and Differentiation, (Just Published), 2020. http://dx.doi.org/10.1038/s41418-020-0542-z


ASYN-CONA, a novel bead-based assay for detecting early stage alpha-synuclein aggregation.

Pérez-Pi, I., Evans, D.A., Horrocks, M.H., Pham, N.A., Dolt, K.S., Koszela, J., Kunath, T., Auer, M.

Analytical Chemistry, 91, 9, 5582-5590, 2019. http://dx.doi.org/10.1021/acs.analchem.8b03842


Nanoscopic characterization of individual endogenous protein aggregates in human neuronal cells

Whiten, D.R., Zuo, Y., Calo, L., Choi, M., De, S., Flagmeier, P., Wirthensohn, D.C., Kundel, F., Ranasinghe, R.T., Sanchez, S.E., Athauda, D., Lee, S.F., Dobson, C.M., Gandhi, S., Spillantini, M., Klenerman, D., Horrocks, M.H.

ChemBioChem, 19, 2033-2038, 2018. http://dx.doi.org/10.1002/cbic.201800209


Extrinsic Amyloid-Binding Dyes for the Detection of Individual Protein Aggregates in Solution

Taylor, C.G., Meisl, G., Horrocks, M.H., Zetterberg, H., Knowles, T.P.J., Klenerman, D.

Analytical Chemistry, Just Published, 2018. http://dx.doi.org/10.1021/acs.analchem.8b02226


Single-Molecule Characterization of the Interactions between Extracellular Chaperones and Toxic alpha-Synuclein Oligomers

Whiten, D.R., Dezerae, D., Horrocks, M.H., Taylor, C.G., De, S., Flagmeier, P., Tosatto, L., Kumita, J.R., Ecroyd, H., Dobson, C.M., Klenerman, D.

Cell Reports, 23, 3492-3500, 2018. http://dx.doi.org/10.1016/j.celrep.2018.05.074


alpha-Synuclein Oligomers Interact with ATP Synthase and Open the Permeability Transition Pore in Parkinson's Disease

Ludtmann, M. H. R.*, Angelova, P. R.*, Horrocks, M. H.*, Choi, M. L., Rodrigues, M., Baev, A. Y., Berezhnov, A. V., Yao, Z., Little, D., Banushi, B., Al-Menhali, A.S., Ranasinghe, R.T., Whiten, D.R., Yapom, R., Dolt, K.S., Devine, M.J., Gissen, P., Kunath, T., Jaganjac, M., Pavlov, E.V., Klenerman, D., Abramov, A.Y., S. Gandhi, S. *Joint first authors

Nature Communications, 9 (1), 2293, 2018. http://dx.doi.org/10.1038/s41467-018-04422-2