Programme 1: Trazodone

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Stand A: Scientific Discovery Programme

Research Programme 1

Mechanisms of trazodone action and PERK activation for drug treatments of Parkinson-Plus diseases

Lead: Professor Giovanna Mallucci

The unfolded protein response (UPR), particularly the PERK branch, has recently emerged as an important neurotoxic pathway across the spectrum of neurodegenerative diseases, from Alzheimer’s to Parkinson-Plus disorders.

The Mallucci Laboratory has pioneered discoveries pertaining to both the mechanism of brain cell damage due to PERK branch UPR activation and the use of experimental drugs to inhibit its activation in these diseases. These have led to the discovery that the licensed antidepressant drug trazodone is an effective inhibitor of this pathway, able to confer neuroprotection in mouse models of disease.

As trazodone is already in clinical use for other conditions, it can now be repurposed as a novel treatment for neurodegenerative diseases. To ensure the greatest success of this approach for patients and to optimize clinical trial design, we will perform the following programme of work, including pre-clinical and clinical projects.

See also Clinical Trial C.

Methods

  • Cellular thermal shift assay (CETSA) to provide an unbiased target engagement identification for trazodone in a physiologically relevant environment 
  • Once candidate targets have been identified, we will triage these using a 5-step process, in collaboration with the ARUK Cambridge Drug Discovery Institute (DDI)
  • Structural, biochemical, biophysical, and in vivo techniques to develop a comprehensive understanding of the mechanisms engaged by PERK activation

Related publications

  • Freeman, O. J., & Mallucci, G. R. (2016). The UPR and synaptic dysfunction in neurodegeneration. Brain Res, 1648(Pt B), 530-537. doi:10.1016/j.brainres.2016.03.029
  • Halliday, M., Hughes, D., & Mallucci, G. R. (2017a). Fine-tuning PERK signaling for neuroprotection. J Neurochem. doi:10.1111/jnc.14112
    Halliday, M., & Mallucci, G. R. (2014). Targeting the unfolded protein response in neurodegeneration: A new approach to therapy. Neuropharmacology, 76 Pt A, 169-174. doi:10.1016/j.neuropharm.2013.08.034
  • Halliday, M., & Mallucci, G. R. (2017). Reply: Trazodone to change the risk of neurodegeneration: bedside to bench. Brain, 140(8), e48. doi:10.1093/brain/awx150
  • Halliday, M., Radford, H., Zents, K. A. M., Molloy, C., Moreno, J. A., Verity, N. C., Smith, E., Ortori, C. A., Barrett, D. A., Bushell, M., & Mallucci, G. R. (2017b). Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain, 140(6), 1768-1783. doi:10.1093/brain/awx074
  • Hughes, D., & Mallucci, G. R. (2018). The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway. FEBS J. doi:10.1111/febs.14422
  • Radford, H., Moreno, J. A., Verity, N., Halliday, M., & Mallucci, G. R. (2015). PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol, 130(5), 633-642. doi:10.1007/s00401-015-1487-z
  • Smith, H. L., & Mallucci, G. R. (2016). The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain, 139(Pt 8), 2113-2121. doi:10.1093/brain/aww101
  • Moreno, J. A., Halliday, M., Molloy, C., Radford, H., Verity, N., Axten, J. M., Ortori, C. A., Willis, A. E., Fischer, P. M., Barrett, D. A., & Mallucci, G. R. (2013). Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med, 5(206), 206ra138. doi:10.1126/scitranslmed.3006767
  • Moreno, J. A., Radford, H., Peretti, D., Steinert, J. R., Verity, N., Martin, M. G., Halliday, M., Morgan, J., Dinsdale, D., Ortori, C. A., Barrett, D. A., Tsaytler, P., Bertolotti, A., Willis, A. E., Bushell, M., & Mallucci, G. R. (2012). Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration. Nature, 485(7399), 507-511. doi:10.1038/nature11058