Stem Cells, Prion Proteins and Alzheimer's Diseases: A Prion Chemical Biology Network (PCBNet)

Cellular prion protein, PrPC, is a membrane-anchored glycoprotein encoded by the human Prnp gene located on chromosome 20. PrPC is expressed ubiquitously, but at significantly higher levels in neuronal cells. It is highly conserved across vertebrates and has been shown to exhibit a diverse range of biological activities associated with many developmental processes and a number of normal and abnormal conditions including memory, neuroprotection, Transmissible spongiform encephalopathy (TSE), Alzheimer's diseases (AD) and cancer etc.

Unfortunately, the exact mechanisms for each of the above normal or abnormal conditions are yet to be confirmed despite significant investment from research councils and government. Contributing to this lack of understanding is a dearth of breakthroughs in prion chemical biology research. Prion research over the past decade has been coordinated by joint funders (EPSRC, BBSRC, MRC, and Department of Health, DEFRA and other major research councils and charity) with a very broad remit mainly focusing on TSE research. As a result, many other prion related research areas are less well coordinated and severely underfunded. Here we propose to establish a prion chemical biology network to promote multidisciplinary collaborative research underpinning the role of prion protein in stem cell and development and ageing-related neurodegenerative diseases such as AD, so as to provide a platform for the rapid translation of underpinning research into prion related drug discovery and intervention towards regenerative medicine and combating neurodegenerative disease. Building up strong consortia to attract more future research funding will be the key outcome of this proposed network.

The network will seek to drive prion chemical biology research into two relatively new areas of relevance to the ageing society and in personalised medicine, building on the advances in understanding, skills and facilities developed in the study of transmissible spongiform encephalopathy (TSE) over recent years: 1)The normal physiological role of prion protein in the behaviour and function of stem cells and in embryonic development; 2)The role of prion protein in ageing and neurodegenerative diseases, e.g. Alzheimer's disease (AD) and TSE.

The over arching objective of the proposed network is to enable the scientific community to expand its understanding of the role of prions in biology and to accelerate progress to new diagnostic and therapeutic tools for the improvement of human and animal health. The achievement of these objectives will be reliant on the engagement of several stakeholder groups. These groups include: the scientific community, commercial organisation user groups, charities, interest groups and the general public. The development of a network dedicated to the advancement of prion chemical biology would benefit each of the aforementioned stakeholder groups.
The benefit to the UK research community of the PCBNet is that it provides a forum in which chemists, biologists, engineers and medical experts can discuss, exchange and explore ideas in prion chemical biology. The realisation of the network objectives requires a collaborative multidisciplinary approach, which will be assisted by the proposed composition of the research themes. The network will act as a platform for real multidisciplinary collaboration to occur. Collaborative research in general, allows researchers to break out of their traditional restrictive boundaries, these interdisciplinary areas are key to translating research into real life situations. The network members will collaboratively generate concept notes, which will be delivered to funding bodies with the aim of shaping future funding calls. The network will also provide an opportunity for members to create consortiums to apply for large funding opportunities, engaging with both other academic research groups and commercial partners. The PCBNet will provide funding opportunities for small projects to help establish these new research partnerships.
Cellular prion proteins, PrPc, have long been associated with a family of fatal neurodegenerative diseases called Transmissible spongiform encephalopathy (TSE), more recently PrPc have been linked to Alzheimer's disease. The network will build upon existing research into TSE's to advance understanding into the role PrPc plays in the development of age related and neurodegenerative diseases. In the case of the general public the achievement of the network objectives and advancement in the understanding of age related diseases would have a direct and beneficial effect. Advancement in diagnostic techniques and therapeutic tools would result in an increased life expectancy and standard of living for Alzheimer's patients. The benefits to the interest group stakeholders, for example the Alzheimer's Society are similar in that the development of such a network has the potential to progress research into the causes, cures and prevention of these conditions. Several interest groups have accepted invitations to sit on the PCBNet management committee, this will provide these groups the opportunity to help steer the focus of the network, the acceptance of these invitations illustrates that these groups recognise and appreciate the importance of such a network.
The potential of a network dedicated to the furthering the understanding of prion proteins has been acknowledged by industry representatives from Eli-Lilly and AstraZeneca, both world leading pharmaceutical companies and from smaller commercial partners AFChemPharm and Retrogenix. The benefit of the network to commercial partners is that it will provide an opportunity to collaborate with a multidisciplinary team of experts and potentially provides early access to non-confidential research results. As the UK population ages, age related diseases will become increasingly common as such the social and economic benefits to the UK in developing treatments for these conditions could be huge.