Mechanisms of neurotoxicity
Programme Leader: Giovanna Mallucci
Programme Leader: Professor Giovanna Mallucci MD PhD
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.