Neurodegenerative disease is becoming an increasing burden on healthcare and there is a continuing need to understand the cellular mechanisms involved and generate new therapeutic approaches. One important question to address is why distinct populations of neurons are vulnerable in these disorders despite widespread expression of the proteins involved.
The aim of our research is to understand the molecular pathways that underpin this common theme in neurological disease using a combination of cell biology and new mouse models.
In recent years there has been a particular focus on the role of reactive oxygen species as factors that mediate the differential susceptibility of neurons. Indeed, oxidative stress and mitochondrial dysfunction have been implicated in all major neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Parkinson’s and Alzheimer’s disease. Furthermore, several pathogenic mutations in proteins that feature prominently in antioxidant pathways have been described in these disorders. Therefore, identification of pathways that counteract oxidative damage may identify new therapeutic strategies that are widely applicable to human disease.
A new Molecular Neurobiology Group is being established at the MRC Harwell Institute from April 2017. The research programme is focused on a family of proteins that we have shown to be important for controlling the stress response in neuronal cells. We have demonstrated that deletion of the protein oxidation resistance 1 (Oxr1) causes neurodegeneration in mice, yet conversely, over-expression of Oxr1 is protective in cellular and mouse models of ALS. Oxr1 contains the TLDc domain, a motif present in a family of proteins including TBC1 domain family member 24 (TBC1D24), a protein mutated in a range of disorders characterised by seizures, hearing loss, and neurodegeneration. The TLDc domain is highly conserved across species, although the structure-function relationship is unknown. To understand the role of this domain in the stress response and disease, we are carrying out systematic functional analysis of TLDc domain-containing proteins as well as investigating their neuroprotective properties in mouse models of neurodegeneration.
For further information about our current and previous research click here.
Image shows neuromuscular junctions in a mouse model of ALS (Matthew Williamson)