Tau aggregation in Drosophila and rodent models of Tauopathy
The overarching goal of this project is to study the process by which physiological monomeric tau becomes abnormal and polymerises to form aggregates in both rodent and Drosophila models of tauopathy. A key objective is to identify the different tau species that emerge as the disease evolves and delineate their causal role in the pathogenic process.
Conformational fingerprinting of tau species
Several lines of evidence indicate that misfolded tau can form a number of conformationaly distinct intermediates leading to structurally distinct fibrillary pathology in different tauopathies. Little is known about the conformational composition of such intermediate species. The aim of this project is to utilize different biophysical technologies to study the conformation of different tau conformers with a view to using conformational fingerprinting for their unique identification. It is a key part of an ongoing inter-disciplinary collaboration between the Mudher lab in the Biological Sciences and the Mahajan lab in the department of Chemistry at the University of Southampton.
Propagation of tau pathology in Drosophila models
This project seeks to exploit the genetic tractability of Drosophila to dissect the mechanisms that underpin the trans-synaptic propagation of tau pathology in vivo. It is a collaboration between the Mudher lab in Southampton and the Allan lab at the University of British Columbia, bringing together expertise in tau biology and cutting-edge Drosophila genetics.
What underpins neuronal vulnerability to tau pathology?
Tau pathology does not appear to affect all neuronal populations in the human brain to the same extent. Some brain regions are clearly more vulnerable and affected early on in Alzheimer’s disease, whilst others appear more resistant and are unaffected until the very late stages of neurodegeneration. Using a very elegant set of genetic tools that enable tight temporal and spatial control of gene expression at the level of individual neurons, Lovesha Sivanantharajah, the Alzheimer Society junior fellow who is conducting this research, seeks to identify neuronal sub-populations that are resistant and those that are vulnerable to development of tau pathology. Her aim is to delineate the mechanism(s) responsible for vulnerability and resistance. This project is an ongoing collaboration between the Shepherd lab at the University of Bangor, where this work is conducted, and the Mudher lab.
Causal relationship between type-2 diabetes and AD
It is well known that individuals with type-2 diabetes are at increased risk of developing Alzheimer’s disease. However the mechanistic link underpinning this comorbidity is unclear. This project investigates one potential link potentially mediating the cross talk between the pathways affected in type-2 diabetes and those involved in tau phosphorylation and clearance in both Drosophila models and human brain tissue.
How do neurons age?
Aging is by far the greatest risk factor for developing age-related neurodegenerative diseases. Many neuronal structures and cellular pathways are implicated in aging and are shown to be altered in the brains of patients with neurodegeneration. However, relatively little is known about how such neuronal structures and cellular pathways are altered during physiological aging, and how a deviation from this norm may pave the way for the pathological change seen in neurodegenerative disease. Answering these and related questions is the primary focus of this project.