Proteostasis

The Cambridge Drug Discovery Institute is focused on understanding and manipulating proteostasis.

Targeting proteostasis mechanisms for the treatment of neurodegeneration.

The Cambridge DDI is developing new approaches to slow or halt the progress of the diseases that cause dementia. Our primary focus is to explore mechanisms associated with the misfolded, aggregated proteins which characterise most neurodegenerative diseases.

There is strong evidence that the misfolded and oligomerised forms of proteins such as tau (Alzheimer’s disease and other tauopathies), huntingtin (Huntington’s disease) and α-synuclein (Parkinson’s disease, dementia with Lewy bodies) are key species responsible for driving the development of the diseases that cause dementia.

We are focussed on understanding and manipulating proteostasis – the mechanisms which control the levels, structure and toxicity of these proteins. We are working with academics who are exploring proteostasis pathways and mechanisms such as:

  • Factors affecting the overall levels of these proteins, particularly clearance mechanisms such as proteosomal clearance and autophagy, this latter process being capable of removing larger oligomeric or aggregated species. We are developing methods to increase the rate at which the misfolded proteins are cleared through these mechanisms.
  • The role of chaperone proteins that help the folding and unfolding of their client proteins. We are exploring approaches to increasing chaperone activity.
  • The role of post-translational modifications of these proteins which can affect rates of clearance and of aggregation. Can we learn how to control these modifications to reduce levels of the unwanted toxic species?
  • The response of cells to the stress associated with the build-up of unfolded proteins and the resultant impact on general proteostasis, known as the unfolded protein response, is known to be a critical factor in the toxicity associated with misfolded proteins.