New Tools to Study Disease-Related Protein Fibril Growth and Inhibition

Lead Research Organisation: University of Bath
Department Name: Chemistry


Misfolded proteins aggregate within the central nervous system and form plaque like structure that facilitates toxicity
and autoimmune response, both of which results in hole-like lesions that are signature of neurodegenerative
Inhibiting the aggregative events during fibril formation remains an effective strategy to prevent neurodegeneration.
However, the exact mechanism of fibril formation and inhibitor action remain elusive to researchers. By developing
better techniques to study fibrils, it is hopeful that the data will improve existing inhibitor designs or provide new drug
targets for neurodegeneration. Hence the need for 'new tools to study disease-related protein fibril growth and
This PhD project is a collaboration between Dr Adam Squires (Department of Chemistry) and Dr Jody Mason
(Department of Biology & Biochemistry). The student will advance the development of biophysical methods
pioneered in the Squires lab to study amyloid protein aggregation, and apply them to therapeutic small peptide-based
aggregation inhibitors for Parkinson's disease, rationally designed by a peptide fragment library screening system
developed in the Mason group.
The student will develop novel isotope labelling strategies for neutron scattering and other relevant spectroscopy
techniques to obtain previously unobtainable data on fibril growth rates in solution and molecular arrangement within
Using these tools, they will elucidate the mode of action of the therapeutic inhibitors, with additional complementary
biophysical methods based on fluorescence assays, NMR, mass spectrometry, and small-angle x-ray scattering
using Bath's new small-angle x-ray scattering instrument.
They will use the resulting data to address key questions:
- how do therapeutic peptides inhibit aggregation? (By preventing formation of new fibril "seeds" or slowing down
their subsequent growth?)
- What is the structural and energetic basis for peptide binding? Towards which (non-toxic) species does the peptide
drive the alpha-synuclein?
In addition to the insights gained into this potentially important class of therapeutic agent, the project will develop and
demonstrate experimental tools applicable more generally to a range of systems in biophysics and soft matter.
The student will learn protein expression, and a range of biophysical techniques, including small-angle neutron and xray
scattering in Bath and at national facilities.


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Description In a new diamond Bio-SAXS study, we used SEC-SAXS to extract monomeric forms of alpha-synuclein and H50Q - this is an emerging technique that protects proteins from radiation damage, as well as ensuring that the solution is homogenous - there by increasing the accuracy of our results. We have shown that H50Q unpacks slightly compared to wild type monomers in pH 6.5 - this is likely due to the neutralization of the mutation from histamine to glutamine, there by weaking the interaction between N terminal amphipathic domain and C terminal acidic tail. As a result, the speed of primary nucleation is accelerated as NAC region will likely be exposed prematurely in comparison to wild type monomers. We have also shown that the mutation does not affect its behavior in salt or acidic solutions. Overall, it is evident that the interactions between amphipathic domain and acidic tail is a key factor in driving primary nucleation, and thus could be an important drug target against Parkinson's disease.
Exploitation Route We aim to finalize the analysis of the data from the beam time and hoping to publish a structural paper on alpha-synuclein and its mutant H50Q.
Sectors Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology