JPND: Systems Analysis of Key Nodes in Neurodegenerative Diseases

Lead Research Organisation: Queen Mary, University of London
Department Name: William Harvey Research Institute

Abstract

Neurodegenerative diseases (ND) are characterised by the loss of precise neuronal populations, which at the molecular level can be triggered by alterations in protein homeostasis, defined as changes in protein synthesis, folding and trafficking. Our hypothesis is that although each ND involves distinct culprit proteins and manifests itself in different ways in different brain cells, there exist key common regulatory nodes driving changes in protein homeostasis. Our proposal brings together a multi-disciplinary team, bridging expertise in neuro-receptor function, intracellular protein trafficking regulation, RNA biology, analytical analysis of nerve cells and vesicles, stem cell biology and genomics of mental disorders and systems biology analysis of human diseases. Collaborative partners at Montreal Neurological Institute and Hospital will provide us unique access to neurodegenerative disease patients' stem cells. Our aim is to achieve a systems-level understanding of protein homeostasis regulation across several neurological diseases where altered protein homeostasis is implicated to understand where the similarities and differences occur. Specifically, we will: (i) generate heterologous neuronal populations from ALS/PD/AD and Batten disease patients. This will involve growing-deriving cells for all consortium members; (ii) dissect the control and remodelling of mRNA translation, and the contribution of stress granules in this process, across the disease models; (iii) establish how autophagy, trafficking vesicles and their contents are affected across the disease models; (iv) understand the metabolic and phenotypic impact of the different diseases on neurons and functionally validate if the defects identified in (ii) and (iii) are corrected by manipulating signalling pathways and/or adding neuroprotective agents; and (v) use a systems biology approach to model and map the molecular pathways affected across the disease models to define new regulatory nodes and checkpoints for therapeutic interventions. Such a global comparison of these four diseases will identify common regulatory points for future therapeutic intervention as well as provide novel biomarkers for early onset detection.

Technical Summary

Our working hypothesis is that common checkpoints controlling protein homeostasis go awry in neurological diseases. We aim to understand whether these checkpoints fail for the same or different reasons in each of these diseases. Towards this aim we will tackle the following research questions:
(i) Which differences in mRNA levels, metabolism, and translation, vesicle content or associated trafficking proteins characterise these diseases? (ii) How does neurotransmitter exposure or cell stress influence in each of the NDs alter stress granule function, vesicle content or trafficking protein expression or function? (iii) Are those differences related to genetic vs spontaneous disease onset? and (iv) Can the above data highlight key regulatory nodes that are altered across the diseases?
To answer these questions we have developed the following Aims:
Aim 1: Generate different cell types from mutations that cause AD, ALS, BD, and PD.
Aim 2: Gain a comprehensive understanding of which sets of genes are translationally controlled in response to NDs.
Aim 3: Develop a rigorous model of the intracellular processes that affect chemical transmission in these NDs.
Aim 4: Identify how cell metabolism and cell phenotypes vary across the NDs and how these change depending on the neuroprotective agents provided.
Aim 5: Validation of identified key nodes via pharmacological or genetic intervention.

Planned Impact

In 2010, according to the WHO, neurological disorders comprised 3% of the total global burden of disease, with the top four neurological categories, migraine, epilepsy, dementias, and Parkinson's disease, accounting for 72% of the burden. In Europe, the cost of all brain disorders was estimated at 798 billion euros in 2010 with the global cost of mental health conditions alone estimated at US$ 2.5 trillion, with a projected increase ~US$6 trillion in 2030. There is thus an urgent need for new biomarkers for detection and therapeutic targets in the development of curative drugs, and not just treating the symptoms.

The aim of NEURONODE throughout the duration of the project is to identify novel biomarkers and common nodes of potential therapeutic intervention. Exploitation beyond the duration of the project will involve validating these identified biomarkers in patients and in a larger population study as well as comparing them with other NDs. In addition, we will compare these between sexes. Our long-term goal is to use these biomarkers or drug targets for trials in patients to make a difference in disease detection and treatment.
Benefits patients' health: NEURONODE could provide patients with both new diagnostics for the earlier detection of both disease risk and tests for early onset of the diseases. In addition, NEUROMODE's comparative analysis will inform where there is an opportunity for drug repurposing for novel treatments. The identification of key nodes shared across the diseases will allow rare understudied diseases to benefit from common research on these nodes that may be originally designed for more common NDs.
Other impacts on societal policies: A common problem in research are that resources are often targeted to one disease type, usually the most prevalent. A key outcome of NEURONODE is the identification of common targets across several diseases. Exploitation of these common targets could then be translated to a variety of diseases rather then for only one patient population.
Benefits to the Pharmaceutical industry: We will demonstrate new biomarkers and drug targets that could be pan-disease. We will provide the novel expression data of the various NDs. This will include message and protein turnover, data not usually collected in GWAS type studies. For example, it is currently not known what the top 10 neurotransmitters expressed in several of these NDs. We will provide that from patient cells, valuable information for the drug discovery industry.

Impact and Exploitation plan: The project administrator based at Surrey will evaluate each outcome for its exploitation potential on a case-by-case basis in order to maximise the impact of the project on patient health, the European economy and on future research activities. Scientific impact will be achieved by disseminating our through academic publications in Open Access peer review journals and/or communicated to the general public. The Intellectual Property generated will be protected with the involvement of the relevant Technology Transfer departments of the academic institutions involved. Outcomes that we do not wish to exploit will be directly disseminated to the research community by means of academic publications in Open Access peer review journals and/or communicated to the general public. Software and tools developed for systems biology analysis and not filed for IP protection will be made available to the community via open source conditions.

Publications

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Description JPND NIH collaborative grant
Amount € 224,651 (EUR)
Funding ID JPND_NIH grant: Project MR/S022465/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2019 
End 05/2020
 
Description Mitochondria and ER contact sites 
Organisation University of Cologne
Country Germany 
Sector Academic/University 
PI Contribution We are testing these biosensors in our novel iPS cells. Our contribution is the cells and our time.
Collaborator Contribution They have created and produced and subsequently shared with us a novel biosensor to measure the distances and changes over time between ER and mitochondria. In addition, they have provided us with protocols and their input on the interpretation of the data.
Impact None yet.
Start Year 2019