Antibodies take the strain
This year’s research grant awards
MSA, Parkinson’s and Dementia with Lewy Bodies are called synucleinopathies because all involve the mis-folding and laying down of inclusions in brain cells of a protein called alpha-synuclein. It seems that molecules of this protein, which usually go around in the cells singly, mis-fold and then begin to join together first in small numbers (when the groups of molecules are called oligomers) and then in greater numbers to form fibrils. It is a bit like ‘spoons inside a drawer’. Moreover it seems that once this process begins, unfolded molecules are induced to join in by the initial oligomers. Prion diseases progress this way.
Now in Parkinson’s these aggregates of misfolded alpha-synuclein are laid down in nerve cells (neurons) in particular parts of the brain whereas in MSA they are laid down in a different type of brain cell called glial cells in different parts of the brain and are called Glial Cytoplasmic Inclusions (GCIs). Why the difference? Evidence over the last few years has suggested that alpha-synuclein can misfold in more than one way. This means that there can be various so-called ‘strains’ of this misfolded and aggregated protein. And as you have guessed, a particular strain is believed to have properties that incline it to affect neurons and another has properties that incline it to affect glial cells in other parts of the brain. Glial cells are the sort of cell that supports and nourishes neurons and when they are affected and stop working, neurons also die and the various symptoms of MSA develop.
This project is centred on perfecting the ability to detect the different strains of alpha-synuclein using specially generated anti-bodies. We usually know antibodies as proteins used by the immune system to identify and neutralise foreign objects such as pathogenic bacteria and viruses. But they can be created to recognise and stick like labels to other entities such as our misfolded protein. In this case there has been success in producing antibodies that can bind to particular strains with a good deal of specificity. This project will continue this work and use various novel techniques to detect and make visible in post-mortem brain tissue when this occurs. These new techniques, it is hoped, will enable the researchers to explore and verify the pathological processes involved in MSA at the cellular level especially regarding the role of the different strains of the aberrant protein.
They will then go on to find out whether they can detect the binding of the antibodies to the MSA-specific strain of alpha-synucelin in cerebrospinal fluid (CSF). If so, this would provide a way of confirming, while they were still alive, and ideally at an early stage, that a person had MSA and not, say, Parkinson’s.
Furthermore, once there is a way of firmly diagnosing MSA and tracking its progress, the effect of potential new treatments could be more precisely measured.
In addition the great hope is that specific antibodies could be used to attach to and remove deposited alpha-synuclein – on the assumption that this is a root cause of the disease.
The Project:
Is Multiple System Atrophy a distinct strain of alpha-synucleinopathy?
Lead Applicant:
Prof Steve Gentleman
Department of Brain Sciences, Imperial College London, Burlington Danes Building,
Hammersmith Hospital Campus London
Disclaimer: The views and opinions expressed in the blogs published on these pages are those of the authors and do not necessarily reflect the official policy or position of the MSA Trust.
