High resolution studies to examine the amyloid core and oligomeric intermediates
Lead Research Organisation:
University of Sussex
Department Name: Sch of Life Sciences
Abstract
Proteins are fundamental to almost every biological process in the body and usually adopt a specific three-dimensional structure in order to function. Occasionally, some proteins change their structure and misfold and this may lead to them aggregate or polymerise to form elongated fibres. This type of process is associated with a number of devastating diseases that include Alzheimer's and Parkinson's disease and Bovine spongiform encephalopathy (MSE or 'Mad Cow Disease'). In these diseases the process of misfolding appears to be linked to their progression. The aggregates are made of the body's own proteins and are called amyloid. These amyloid fibrils accumulate causing disruption to the surrounding body tissues. We are interested in what causes normally soluble protein to misfold and to aggregate. In order to understand this better, we are looking at the structure of the final aggregated form, the amyloid. This work is carried out using X-rays, electrons and computer processing. We are also looking at the process of aggregation using a number of different experimental techniques. The aim is to gain a clear picture of the architecture of the amyloid fibril and this will help to understand what causes the fibrils to form and why they are so stable. We can also start to design drugs that can bind and prevent fibril formation.
Technical Summary
Amyloid fibrils are highly ordered and stable aggregates of normally soluble proteins. These fibrous assemblies accumulate in a number of diseases known as the amyloidoses and now more broadly as the misfolding or conformational diseases. There are many proteins and peptides known to form amyloid fibrils in disease and in vitro. These share very little or no sequence homology, yet all form fibres that share common structural features. This infers that primary sequence is relatively unimportant. The fibrils are composed of hydrogen bonded beta-sheet structures and several beta-sheets are held together via side chain interactions. We postulate that the side chain composition of amyloid fibrils has a fundamental affect on the stability and efficiency of formation of the amyloid fibril. Our study focusses on the structural elucidation of core interactions within the amyloid fibril using a model peptide system. Using peptide design methods, we will explore how specific side chain residues contribute to fibril formation and eventual structural order with the fibrils. High-resolution X-ray and electron diffraction with electron microscopy will be used to examine the molecular architecture of the resulting assemblies. Highly ordered arrangements may yield stable structures with potential for use as biomaterials. This model system also provides an ideal opportunity to perform an in depth examination of the early structural intermediates and to probe the importance of primary sequence for their formation and toxicity.
Organisations
People |
ORCID iD |
| Louise Serpell (Principal Investigator) |
Publications
Al-Garawi ZS
(2015)
Silica Nanowires Templated by Amyloid-like Fibrils.
in Angewandte Chemie (International ed. in English)
Al-Garawi ZS
(2015)
Silica Nanowires Templated by Amyloid-like Fibrils.
in Angewandte Chemie (Weinheim an der Bergstrasse, Germany)
Al-Garawi ZS
(2016)
Chemically and thermally stable silica nanowires with a ß-sheet peptide core for bionanotechnology.
in Journal of nanobiotechnology
Bulheller BM
(2009)
Flow linear dichroism of some prototypical proteins.
in Journal of the American Chemical Society
Hubin E
(2015)
Two distinct ß-sheet structures in Italian-mutant amyloid-beta fibrils: a potential link to different clinical phenotypes.
in Cellular and molecular life sciences : CMLS
Jahn TR
(2010)
The common architecture of cross-beta amyloid.
in Journal of molecular biology
Marshall KE
(2011)
Hydrophobic, aromatic, and electrostatic interactions play a central role in amyloid fibril formation and stability.
in Biochemistry
Marshall KE
(2014)
The relationship between amyloid structure and cytotoxicity.
in Prion
Marshall KE
(2016)
A critical role for the self-assembly of Amyloid-ß1-42 in neurodegeneration.
in Scientific reports
Maurer-Stroh S
(2010)
Exploring the sequence determinants of amyloid structure using position-specific scoring matrices.
in Nature methods
Morris KL
(2013)
Exploring the sequence-structure relationship for amyloid peptides.
in The Biochemical journal
Pauwels K
(2012)
Structural Basis for Increased Toxicity of Pathological Aß42:Aß40 Ratios in Alzheimer Disease
in Journal of Biological Chemistry
Soura V
(2012)
Visualization of co-localization in Aß42-administered neuroblastoma cells reveals lysosome damage and autophagosome accumulation related to cell death.
in The Biochemical journal
Vadukul DM
(2017)
Amyloidogenicity and toxicity of the reverse and scrambled variants of amyloid-ß 1-42.
in FEBS letters
Williams T
(2015)
Europium as an inhibitor of Amyloid-ß(1-42) induced membrane permeation
in FEBS Letters
Williams TL
(2011)
Membrane and surface interactions of Alzheimer's Aß peptide--insights into the mechanism of cytotoxicity.
in The FEBS journal
Zibaee S
(2007)
A simple algorithm locates beta-strands in the amyloid fibril core of alpha-synuclein, Abeta, and tau using the amino acid sequence alone.
in Protein science : a publication of the Protein Society
Zibaee S
(2007)
Sequence Determinants for Amyloid Fibrillogenesis of Human alpha-Synuclein.
in Journal of molecular biology
| Description | By studying a range of amyloidogenic peptides and also the Abeta peptide, we were able to show that primary sequence is linked to eventual structure. We revealed that the Abeta peptide is toxic to cells and accumulates in lysosomes and autophagosomes. |
| Exploitation Route | We will continue to better understand amyloidogenesis |
| Sectors | Healthcare |
| Description | Since the work of this grant, we have developed a non-aggregation prone, non-toxic variant of Abeta which has been reported by publication and is covered by a patent. The peptide is currently being licensed to a company. |
| First Year Of Impact | 2016 |
| Sector | Chemicals |
| Description | Soap box science |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Soap box science at Brighton Seafront to talk to the public about our research. Women in Science |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://soapboxscience.org/soapbox-science-2017-brighton/ |