Autoantibody-mediated neuropsychiatric diseases are a rapidly expanding group of potentially treatable conditions which are the major clinical focus of NDCN's Autoimmune Neurology Group.
The group, led by Associate Professor Sarosh Irani, has established neuronal targets of these autoantibodies. Hence, the conditions provide ideal models to delineate the autoantigen-specific B cell lineage as a necessary and sufficient 'pathway to pathogenicity'.
An MRC Senior Clinical Fellowship is a highly prestigious award and only given to those whose work is truly judged to be of international significance. For a single department to produce two successful fellows in one round is an exceptional achievement, and evidence that we are a great research community in which to build a career as a clinician scientist. Many congratulations to George and to Sarosh.
- Professor Kevin Talbot, Head of Department
In this project, Sarosh's group will track autoantigen-specific B cells from their entry into circulation through to their site of pathology in the CNS. In patients, they aim to characterise which cells are potential therapeutic targets, identify stages at which they acquire pathogenicity and generate monoclonal antibodies which are valuable tools for the scientific community. These proof-of-concept findings can readily generalise to understanding the immune contributions in a variety of commoner neuropsychiatric conditions.
Associate Professor George Tofaris' MRC Senior Clinical Fellowship concerns the molecular pathogenesis of Parkinson's disease, a common neurological disorder without cure. In the majority of cases, Parkinson's disease is caused by the accumulation of a small protein called alpha-synuclein and its conversion into clumps called aggregates inside vulnerable neurons. Why some types of neurons are more vulnerable to this process of alpha-synuclein aggregation is not fully understood but it may be related to their inability to clear aggregates efficiently.
The Molecular Neurodegeneration Research Group, led by George, is using induced pluripotent stem cells (iPSC) derived from patients to model such pathological events in human neurons, and genetic screens to decipher relevant pathways that target aggregated alpha-synuclein for destruction. This MRC Fellowship will allow George's team to continue their work on fundamental mechanisms that cause Parkinson's disease.
Specifically, the team will use biochemical and cell-based approaches to determine how aggregate clearance occurs in human neurons and investigate how the cross talk between neurons and other resident brain cells called glia, influence this process. They will study whether aggregate-induced nerve death can be prevented when relevant genes are switched on or off and assess their expression pattern in human brains with early pathology. By improving our understanding of Parkinson's pathogenesis using human models of pathology, the group ultimately aims to identify new therapeutic targets to slow the disease progression in patients.