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Targeting the unfolded protein response as a potential therapeutic in prion disease

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posted on 21.02.2014, 13:38 by Mark Halliday
Many neurodegenerative disorders, including Alzheimer's (AD), Parkinson's (PD) and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. The UPR is a protective cellular mechanism that is induced during periods of cellular and endoplasmic reticulum stress. UPR activation aims to restore protein homeostasis, by reducing protein translation, and up-regulating chaperone proteins that assist with proper protein folding. However, sustained activation of this pathway results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. Inhibiting the UPR by genetic means has recently been shown to be neuroprotective in prion disease (Moreno et al., 2012). A drug screen was performed in the model organism C. elegans to search for inhibitors of the UPR. 34 compounds were identified, of which five were selected for further analysis in C. elegans before being tested as a potential treatment in prion diseased mice. Two compounds, dibenzoylmethane and trazodone hydrochloride displayed efficacy against prion disease, and represent novel therapeutic targets. GSK2606414, a specific inhibitor of PERK (protein kinase RNA-like endoplasmic reticulum kinase), a key mediator of the UPR induced translational repression was also tested in prion diseased mice. It restored protein synthesis and prevented the development of clinical prion disease. These data validate the UPR as a viable target in prion disease, and uncover promising potential therapeutics.

Funding

Medical Research Council (MRC)

History

Supervisor(s)

Mallucci, Giovanna; McDearmid, Jonathan

Date of award

01/01/2014

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

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