Motor neuron disease and frontotemporal disease (MND/FTD) are two overlapping devastating neurodegenerative disease, for which aggregation of TDP-43 is a core feature. However, this pathology is not present throughout the brain, but localised to specific ‘disease vulnerable’ regions. What causes this pathology, and why it is only found in certain neurons, is currently unknown. We have recently found that some of the proteins TDP-43 interacts with differ between disease vulnerable (cortex) and resistant (cerebellum) brain regions. Some of these proteins are known to play roles in the transport of cargoes to and from the cell nucleus – nucleocytoplasmic transport – a pathway already strongly implicated in MND/FTD. This project will explore the interaction of these proteins with TDP-43 in disease vulnerable and resistant brain regions, and investigate whether targeting these proteins may have therapeutic potential for disease.
The aims are:
1. To explore differences in target protein expression and TDP-43 interaction between disease vulnerable and resistant brain regions, and investigate changes in MND/FTD.
2. To assess differences in nucleocytoplasmic transport between disease vulnerable and resistant neurons
3. To investigate whether manipulating target proteins can alter nucleocytoplasmic transport and disease progression
In year 1 the student will work with mouse tissue, carrying out immunohistochemical and western blot analyses, as well as immunoprecipitation and proximity ligation assays, on disease vulnerable and resistant brain regions to address aim 1 using both control and TDP-43 disease model samples. Follow up work will then validate key targets of interest in human post-mortem samples (years 1-2). In year two, the student will use established assays to investigate nucleocytoplasmic transport in cortical, motor and cerebellar neurons derived from induced pluripotent stem cells. In year three, the student will modify selected target proteins in stem cell models and explore the impact on nucleocytoplasmic transport and disease phenotypes.