Protein misfolding diseases
Protein misfolding occurs as a central event in a range of neurological diseases, including Alzheimer’s, Parkinson’s and the transmissible spongiform encephalopathies (prion diseases). We call these designated protein misfolding diseases, or PMDs.
There are currently no effective therapeutics for PMDs. On top of this, preclinical tests are limited and there is a real need to improve biomarkers for effective diagnosis. While the misfolded proteins vary for each disease (amyloid-β and tau in Alzheimer’s, α-synuclein in Parkinson’s and prion protein in prion diseases), the disease mechanisms show established parallels, enabling us to develop common diagnostic and therapeutic methods with distinct PMD applications.
Tackling devastating diseases
Here in the Diagnostics and Therapeutics Research Group, our PMD research is focused primarily on prion diseases. These appear in a number of mammal species and include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease in deer and elk and Creutzfeldt-Jakob disease (CJD) in humans. These diseases can be transmissible or spontaneous.
According to the protein-only hypothesis, the infectious agent of these diseases is formed when a benign cellular prion protein (PrPC) misfolds into a protease-resistant conformation (PrPSc).
These diseases are irreversible and invariably fatal. There is compelling evidence that the BSE agent has crossed the species barrier and is the causal agent of vCJD in humans. In addition, the causal agent appears to be novel – an infectious misfolded version of a host protein which encodes transmissible strain characteristics in the absence of any detectable nucleic acid.
Our specialist research focus
Together we are combatting these diseases across diverse species by investigating:
- Strain typing prion diseases – so we can study emerging strains
- Pre-mortem diagnosis of prion diseases
- Isolation of ligands that can disrupt protein misfolding mechanisms across PMDs
- The cross-seeding ability of distinct misfolded proteins
Spotlight project
Developing highly sensitive diagnostic testing for BSE
As an example of developing novel tests for PMDs, our team is currently developing high-sensitivity diagnostics for BSE in small ruminants who potentially may also have scrapie. Identifying the BSE agent in sheep and goats has always been a considerable challenge, made even more complex when they’re co-infected with classical or spontaneous atypical scrapie.
However, our team has developed a version of the protein misfolded cyclic amplification (PMCA) method that amplifies the BSE form of PrPSc (the infectious agent) without amplifying the scrapie form. The assay shows 97% sensitivity and 100% specificity for the BSE agent, even when it’s present in a 100-fold excess of the scrapie agent. Our assay has been shown to perform better than any other current in vitro statutory test for BSE and provides an additional rapid test for investigating anomalous prion diseases in small ruminants.