Summary of Research Interests
Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease, and also the rarer prion disorders, have enormous clinical and economic impact worldwide. They vary in clinical and pathological hallmarks, including aggregation of misfolded proteins, but in each there is irreversible loss of neurons, which cannot be cured. But before neuronal loss, there is there is synaptic impairment and loss, which potentially can be treated. The mechanisms controlling the causes and progression of synaptic loss to neuronal death are the focus of our research programme.
My background is in modelling prion diseases in mice, looking at mechanisms of neurotoxicity and developing new therapeutic approaches. We have shown that early synaptic changes in mice with prion disease can be reversed, resulting in recovery of synaptic and cognitive function and behavioural deficits, long term neuroprotection, and life long survival of affected animals. Thus neurodegeneration can be prevented by reversing early synaptic deficits.
This programme uses several model systems – mice (wild type and transgenic), primary neurons and the nematode C. elegans, to understand the early molecular events that cause synaptic toxicity and neuronal cell death in neurodegeneration. In parallel, we are looking at the mechanisms involved in synaptic repair processes.
Our main aims are to define:
1) the earliest mechanistic impairments in the neuronal response to toxic proteins in neurodegenerative diseases
2) how synaptic dysfunction and loss are triggered
3) how synapse loss leads to neuronal loss
4) how toxic responses can be reversed for neuroprotection
5) how repair processes can be harnessed for therapy
In this way, we aim to define key pathways for modification in novel therapeutic approaches; to develop mouse models reflecting disease mechanisms; and to define new biomarkers for identifying susceptible individuals.
Background: Modelling mechanisms of neurodegeneration in prion diseases
We previously defined a new therapeutic target for prion disease, the native prion protein, PrPC (1), which is converted to a protease resistant, infectious isoform, PrPSc, that accumulates in the brain during disease. We showed that by targeting PrPC, hence removing the substrate for ongoing prion replication, mice with prion infection can be cured at the stage of early synaptic dysfunction, when they have reversible neurophysiological, behavioural and morphological impairments (2,3). Reversing this early stage of disease allowed long-term neuroprotection and normal lifespan in the mice (2). We were able to do this both in transgenic mice in which PrP was deleted in the adult brain, and by using lentivirally- mediated RNA interference of PrP (4).
These findings set the scene for further analysis: What is the nature of the synaptic deficit that is reversible? What is the window for intervention? What are the mechanisms in neuroprotection? Which pathways are in common with other neurodegenerative disorders that could be modulated for therapy and identification of new biomarkers?
We hypothesize that common pathways govern synaptic and neuronal loss in neurodegenerative disorders, irrespective of specific disease entity. The reversal of early deficits that we have shown in prion disease has far-reaching implications for all neurodegeneration. The long term neuroprotection that results form this reversal strongly supports the concept of a window for intervention at the stage of synaptic dysfunction, in which neurons can be rescued from the early processes that lead to cell death.
Reversal of early morphological, behavioural and neurophysiological deficits in prion diseased mice:
Source:University of Leicester