Our group uses a range of techniques to better understand the cellular and molecular mechanisms of neurodegenerative diseases. Neurodegenerative illness and dementia represent growing public health problems due to our aging population. As the population ages, the number of cases of dementia is set to double within the next 30 years. We are working on the molecular mechanisms of neurodegeneration, focussing initially on three genes: microtubule associated protein tau (MAPT, or tau), alpha-synuclein (SNCA) and leucine rich repeat kinase 2 (LRRK2). Mutations in all three genes cause rare Mendelian forms of neurodegenerative disease, but further study has revealed the proteins play a key role in the more common, sporadic diseases that pose such a large and increasing burden on our society today. More recently, we have initiated projects on two genes specific to Alzheimer's disease: nicastrin (NCT) and presenilin 1 (PS1).

Current Research Programme

The aim of our work is to understand the molecular basis of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, with a view to eventually developing novel molecular therapies. We study the function and dysfunction of MAPT, SNCA, LRRK2, NCT and PS1 in the context of (i) analysis of gene expression at the RNA and protein level in human post-mortem brain tissue; and, (ii) through gene expression and gene function studies in genetic models of neurodegeneration, including neuronal tissue culture models.

tauopathies: Function and dysfunction of the microtubule associated protein tau (MAPT) locus

We are undertaking a functional genomics analysis of the MAPT locus, a gene involved in a variety of neurodegenerative dementias. The MAPT locus is expressed primarily in neurons and accumulation of hyperphosphorylated intracellular tau protein aggregates known as neurofibrillary tangles is seen in neurodegenerative disorders collectively referred to tauopathies. Several independent genetic studies have found an association between the MAPT H1 haplotype variant and the tauopathies progressive supranuclear palsy and corticobasal degeneration, and more recently with Alzheimer's disease and Parkinson's disease. We have now started to uncover the mechanistic link between MAPT haplotypes and susceptibility to neurodegeneration by showing that H1 over-expresses a greater amount of a disease-associated MAPT variant compared to the protective H2 haplotype.

alpha-synucelinopathies: Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and is the basis for another research program. The critical observation in PD pathology is that neurodegeneration is largely restricted to the dopaminergic neurons of the substantia nigra pars compacta which accumulate cytoplasmic inclusions called Lewy bodies composed mainly of the protein alpha-synuclein. The key to understanding PD, therefore, seems to lie in understanding the interaction of alpha-synuclein with dopamine homeostasis.

We are using the technique of RNA interference (RNAi) to knockdown alpha-synuclein expression in human dopaminergic neuronal cultures to better understand the role of alpha-synuclein in dopamine biology. We have shown that RNAi knockdown of alpha-synuclein reduces the velocity of dopamine uptake by the dopamine transporter (DAT) by reducing the number of DAT molecules at the cell surface. Furthermore, we have shown that this protects dopaminergic cells from neurotoxic insult by MPP+, a DAT-dependent neurotoxin. Our ideas may one day form the basis for a novel PD therapy.

Gene therapy

Our group has long had an interest in improving episomal, non-integrating gene expression systems, both viral and non-viral, to allow routine expression of complete genomic loci for gene therapy and functional genomics. Our laboratory has pioneered the development of a novel high-capacity vector system for the delivery of bacterial artificial chromosome (BAC) genomic DNA inserts by herpes simplex virus type 1 (HSV-1) amplicon vectors. The vector system is named the infectious BAC, or iBAC, vector and forms the basis for on-going projects in the laboratory developing gene therapies for the treatment of familial hypercholesterolaemia and Friedreich's ataxia.

Familial hypercholesterolaemia

We are developing viral (iBAC vectors) and non-viral (hydrodynamic delivery of BAC vectors) methods of liver-directed expression of the low density lipoprotein receptor (LDLR) genomic DNA locus as a potential therapy for familial hypercholesterolaemia in collaboration with Professor Keith Channon (Department of Cardiovascular Medicine, University of Oxford). Delivery and expression of the LDLR gene using the entire genomic locus will allow long-term therapeutic gene expression regulated by cellular sterol levels.

Friedreich's ataxia

We are developing an HSV-1 gene therapy approach to treat the neurological deficits of Friedreich's ataxia (FA) in collaboration with Dr Filip Lim (Autonomous University of Madrid, Spain). We have recently demonstrated in vitro that delivery and expression of the complete FA genomic locus (FRDA) from the iBAC-FRDA vector can complement the cellular phenotype of primary FA patient fibroblasts. We will now follow this work up and develop further models of FA.

Further information on all our research can be found at: https://www.neuroscience.ox.ac.uk/directory/richard-wade-martins

Richard Wade-Martins