Background
The failure of proteins to fold into their functional forms leads occasionally to “misfolding” or “conformational” diseases. Many among the most common and debilitating of these diseases are associated with the formation of protein amyloid, an insoluble material that is deposited as fibrils or plaques in different body tissues and organs. Amyloid formation is known to be accelerated by a variety of cellular factors, including metal ions, such as copper and zinc, and interactions with other species, such as lipids and RNA.
Aberrant folding can lead to protein aggregates deposited inside or outside cells, and is the cause of several neurological and systemic diseases (e.g. Alzheimer’s disease and the transmissible prion disorders) compromising the quality of life and the health resources of society.
The number of diseases now known to be associated with misfolding is large and increasing all the time (Table 1). Understanding the processes responsible for the failure to achieve or maintain the normal functional structures of proteins is crucial for developing strategies to protect or enhance human health.
| Clinical Syndrome | Fibril Component |
|---|---|
| Alzheimer’s disease | Aβ peptide, 1–42, 1–43 |
| Spongiform encephalopathies | Full-length prion or fragments |
| Senile systemic amyloidosis | Wild-type transthyretin and fragments |
| Familial amyloidotic polyneuropathy I | Transthyretin variants and fragments |
| Type II diabetes | Fragment of islet-associated polypeptide |
| Haemodialysis-related amyloidosis | β2-microglobulin |
| Medullary carcinoma of the thyroid | Fragments of calcitonin |
| Atrial amyloidosis | Atrial natriuretic factor |
| Atrial amyloidosis | Full-length insulin |
Project Task
The tools will be applied to representative proteins associated with misfolding diseases, ranging from natively unfolded species (a-synuclein associated with Parkinson’s) and partially unfolded intermediates (forms of superoxide dismutase associated with motor neurone disease) to the precursors of aggregation prone fragments (the Alzheimer precursor protein) and the prion proteins uniquely associated with transmissible conditions.
A major aim is to provide a novel unified view of the conformational behaviour of proteins that will have a broad significance for understanding important aspects of functional genomics, including the fundamental links between genetic mutations and disease and the mechanisms by which normally soluble proteins can sporadically misfold, giving rise to a range or disorders associated with diet, medical and agricultural practices and ageing.
Graphical Presentation
