New thesis about understanding how the molecular chaperone domain BRICHOS can prevent aggregation and toxicity of disease-relevant proteins
Hi Axel Leppert, PhD student at the Division of Neurogeriatrics! On December 11 you will defend your thesis “Molecular basis for chaperone activities of the BRICHOS domain against different types of clumpy clients – a route to prevent amyloid toxicity”. What’s the main focus of the thesis?
Structurally diverse aggregates, formed by different proteins, are found as deposits in many devastating human diseases, like Alzheimer’s disease (fibrillar aggregates) or cataract of the eye lens (non-fibrillar aggregates). Luckily, nature gave us protein tools to regulate and prevent unwanted aggregation, the so-called molecular chaperones.
My thesis focuses on understanding how the molecular chaperone domain BRICHOS is able to prevent structurally different types of protein aggregation and mitigate their toxic effects.
Which are the most important results?
Firstly, we found that the BRICHOS domain is able to exist as a single domain (monomer) or in several assembly states made up of multiple BRICHOS subunits (oligomer) that have distinct activities to interfere with fibrillar or non-fibrillar protein aggregation. Secondly, we found that the conversion from monomers to oligomers is triggered by reductive stress conditions. We then engineered different variants of the BRICHOS domain that improve the stability and efficiency of the monomer conformation, in order to modulate toxic effects of fibrillar protein aggregation.
How can this new knowledge contribute to the improvement of people's health?
Increasing the molecular chaperone capacity of an organism is potentially a promising way to modulate the disease progression of aggregation associated disorders for which to date no curative treatment has been found.
What's in the future for you? Will you keep on conducting research?
I have always had a keen interest in biochemistry and biophysics, and I would like to continue studying and understanding the basic mechanisms of how molecular chaperones function. For the future it would be nice to learn some additional methods for protein analysis, like mass spectrometry.