Principal Investigators

    Professor Giovanna Mallucci


    University of Cambridge

    Contact information of lead PI


    United Kingdom

    Title of project or programme

    Repurposed drugs targeting the unfolded protein response to prevent neurodegeneration in dementia

    Source of funding information

    Alzheimer's Society

    Total sum awarded (Euro)

    € 115,462

    Start date of award


    Total duration of award in years



    Research Abstract

    We recently discovered the mechanism by which protein misfolding leads to neurodegeneration in prion
    disease. The pathway involved is a generic cellular pathway, a branch of the unfolded protein response (UPR)
    that controls protein synthesis at the level of initiation of translation. Rising levels of misfolded prion protein
    cause sustained over-activation of the PERK-eIF2? branch of the UPR in neurons resulting in an
    uncompensated decline in global translation rates, synaptic failure and neuronal death. Reduction of eIF2?- P
    levels by genetic manipulation or by pharmacological inhibition of PERK by GSK2606414, rescue vital
    translation rates and prevent neurodegeneration and clinical disease in prion-infected mice. The small
    molecule ISRIB is similarly protective. There is increasing evidence that UPR dysregulation is a central
    process in protein misfolding neurodegenerative diseases, and that maintaining translation levels is essential
    for neuronal health. Raised levels of PERK-P and eIF2?-P occur in the brains of patients with Alzheimer’s,
    Parkinson’s, Frontotemporal dementias and related diseases. The pathway is also implicated in learning and
    memory; manipulation of eIF2?-P levels boost cognition in wild type mice and restore memory deficits in AD
    mouse models. Raised levels of eIF2?-P are associated with neurodegeneration in a tauopathy mouse model,
    which we have also prevented by treatment with PERK inhibitor. However, progressing these compounds to
    clinical use has been impeded by pancreatic toxicity of GSK2606414, and poor solubility of ISRIB. This led us
    to screen known drug libraries for inhibitors of the UPR in C. elegans and cell lines with better therapeutic
    qualities. Two compounds, trazodone and dibenzoylmethane, were found and tested in prion disease and
    displayed efficacy without toxicity. Trazodone is an antidepressant that could be repurposed for the treatment
    of dementia, while dibenzoylmethane is a naturally occurring compound with low toxicity. The aim of this
    application is to test these compounds in models of tauopathy and Alzheimer’s disease, to determine their
    greater relevance to dementia and to strengthen the case for repurposing these compounds for new
    therapeutic treatments.

    Further information available at:

Types: Investments < €500k
Member States: United Kingdom
Diseases: N/A
Years: 2016
Database Categories: N/A
Database Tags: N/A

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