For Parkinson’s Awareness Month, we asked BPS member David Klenerman, a professor in the chemistry department at Christ’s College, University of Cambridge, to talk about the work going on in his lab related to the disease.
What is the connection between your research and Parkinson’s disease?
We are studying how alpha synuclein, a protein thought to play a key role in the disease, aggregates to form small soluble oligomers and finally fibrils, and how these soluble oligomers interact with neuronal cells and damage them. Only about 1% of the molecules present make up the oligomers, which are highly heterogeneous, existing in different structures and sizes. This makes them very challenging to study, so we use fluorophore-labeled alpha synuclein and single molecule fluorescence to detect and characterize them.
Why is your research important to those concerned about these diseases?
Understanding how alpha synuclein aggregates, which oligomers are damaging, and how they damage cells would allow the rational design of therapies to prevent either their formation, or prevent them damaging neurons.
How did you get into this area of research?
Our interest in protein misfolding and neurodegeneration started when Chris Dobson moved to the Department with his group about 10 years ago now. This seemed a problem where single-molecule fluorescence might be well placed to provide new insights, and Chris’ group had the expertise to label and aggregate the proteins of interest
How long have you been working on it?
About 10 years now. The first system we chose to study, a 10 amino acid sequence, was unstable when diluted down to the picomolar concentrations, and so it took a couple of years to find a system in which the oligomers were stable enough to study. When we moved onto the proteins such as alpha synuclein and beta amyloid, which are involved in neurodegenerative diseases, they turned out to be more stable and the experiments became easier
How is your work funded?
We were fortunate to be included in a consortium on Alzheimer’s disease funded by the MRC and Wellcome trust which allowed us to work with electrophysiologists and clinical neuroscientists and helped focus our work on the important questions in the field. The MRC Wellcome trust also funded a consortium on Parkinson’s disease and encouraged us to work with this consortium using our single-molecule methods and we now have an active collaboration with Nick Wood’s group at UCL on Parkinson’s disease.
Have you had any surprise findings thus far?
Our work has shown that the oligomers undergo a slow conversion step from a globular to what we believe is an extended beta sheet structure, which is more stable ,and much more toxic to cells. This conversion takes about a day and a half, and so is very slow compared to the folding of proteins into their native state.
What is particularly interesting about the work from the perspective of other researchers?
It is very exciting that single-molecule fluorescence methods can be used to start to provide new insights into human disease. The molecular processes that we are studying apply to other neurodegenerative diseases such as Alzheimer’s and are probably involved in ageing in general. These methods can also be used to test potential drug candidates that inhibit aggregation or interact directly with the oligomers reducing cellular damage.
Do you have a cool image you want to share with the blog post related to this research?
The image at the beginning of this poist shows the microfluidic device we have designed and made for our single molecule experiments.