Ordering the disordered in Parkinson's disease to derive peptide inhibitors of alpha-synuclein toxicity
Lead Research Organisation:
University of Bath
Department Name: Biology and Biochemistry
Abstract
The student will develop peptides that can be used to effectively block formation of a toxic protein responsible for the
pathology of Parkinson's disease (PD). The protein, known as alpha-synuclein (aS), self-associates inside dopamine
producing cells in the brain to form toxic clumps known as Lewy bodies that interfere with normal brain function, leading
to the symptoms of the disease. We will inhibit this process building from a system that we have demonstrated to work
(Meade et al J Mol Biol 2021, 2022, Watt et al ACS Chem Neurosci 2022, Watt et al J Biol Chem 2022). Using a novel
screening system that targets the natural folded state of aS, that is prior to misfolding and aggregation, the student will
screen large peptide libraries (>2 Million members) inside living bacterial cells. In this assay, inhibitors are only selected if
the very first step in aggregation is blocked, leading to a restoration of cell viability.
The student will use the screening assay to generate numerous inhibitory peptides to block the very first steps in the
misfolding of aS. This will provide a wide range of sequences from which we can understand the mechanism of inhibition
via biophysical, neuronal cell-based, and structural biology methods. Our overarching aim is to assign function to specific
sequence elements within our newly generated inhibitors to demonstrate the principles of rational inhibitor design,
ultimately improving the properties of future peptide generations. Finally, by comparing endogenously produced to
externally added peptides, the student will begin to explore aspects of drug delivery, such as permeability to reach
intracellular targets. The composition of the supervisory team ensures comprehensive expertise in all facets of this
interdisciplinary project. The training environment will be highly supportive and stimulating, including ample
opportunity for wider engagement with the scientific community. You will be guided through the challenges and
rewards of this project while gaining a wide range of skills that are translatable to many other systems.
pathology of Parkinson's disease (PD). The protein, known as alpha-synuclein (aS), self-associates inside dopamine
producing cells in the brain to form toxic clumps known as Lewy bodies that interfere with normal brain function, leading
to the symptoms of the disease. We will inhibit this process building from a system that we have demonstrated to work
(Meade et al J Mol Biol 2021, 2022, Watt et al ACS Chem Neurosci 2022, Watt et al J Biol Chem 2022). Using a novel
screening system that targets the natural folded state of aS, that is prior to misfolding and aggregation, the student will
screen large peptide libraries (>2 Million members) inside living bacterial cells. In this assay, inhibitors are only selected if
the very first step in aggregation is blocked, leading to a restoration of cell viability.
The student will use the screening assay to generate numerous inhibitory peptides to block the very first steps in the
misfolding of aS. This will provide a wide range of sequences from which we can understand the mechanism of inhibition
via biophysical, neuronal cell-based, and structural biology methods. Our overarching aim is to assign function to specific
sequence elements within our newly generated inhibitors to demonstrate the principles of rational inhibitor design,
ultimately improving the properties of future peptide generations. Finally, by comparing endogenously produced to
externally added peptides, the student will begin to explore aspects of drug delivery, such as permeability to reach
intracellular targets. The composition of the supervisory team ensures comprehensive expertise in all facets of this
interdisciplinary project. The training environment will be highly supportive and stimulating, including ample
opportunity for wider engagement with the scientific community. You will be guided through the challenges and
rewards of this project while gaining a wide range of skills that are translatable to many other systems.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/T008741/1 | 01/10/2020 | 30/09/2028 | |||
| 2892099 | Studentship | BB/T008741/1 | 01/10/2023 | 30/09/2027 | Lucy WHITE STENNER |