Investigating synaptic health over time in neurodegeneration to identify dysfunctional mechanisms and early stage modifiable therapeutic targets.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% of over 65's; there is currently no effective treatment. One of the major features initially identified in PD was the loss of a set of neurons in an area known as the substantia nigra. These neurons produce a chemical known as dopamine which helps to control movement and behaviour, thus the loss results in the classic clinical motor symptoms. For a long time, the focus of research was aimed at halting, preventing or bypassing cell death. From this research, the potent drug L-DOPA was developed. This replaces the lost dopamine in the brain and reduces the motor symptoms for a period of time. However, the effectiveness of the drug diminishes over time, and it does not prevent further degeneration. This solution is therefore temporary and the drug may even leave patients with new symptoms. This is almost certainly because the drug targets what happens at late stages of PD i.e. cell death rather than the cause of the cell death.
Recent work shows that altered function (dysfunction) comes well before neurons die. Areas of the brain affected in PD controls reasoning as well as movement, & changes in behaviour are seen in individuals with PD long before motor symptoms are shown. Understanding what is at the heart of these changes will enable us to work out the cause of the disorder.
The aim of this work is to provide a change in the approach to PD research by identifying early changes in neuron function that can be targeted in order to truly halt or prevent clinical symptoms of PD.
The fundamental role of neurons is to communicate via electrochemical circuits. Dysfunction of these circuits would result in the behavioural changes observed early in PD & contribute to the motor symptoms seen later in the disorder. This electrochemical communication also sets neurons apart from nearly every other cell in the human body. Since neurons specifically malfunction & die in PD, it is probably their specialised role that may make them specifically vulnerable. As a result, incorrect operation of these circuits these neurons are involved in is the most likely place to observe early changes in PD, & drugs that target these early changes may be capable of stopping the ongoing degeneration seen in PD, or preventing irreversible damage altogether.
In order for us to measure changes in neuronal circuitry, we will use cutting edge electrophysiology technology. This allows us to measure the electrical communication of the brain by making a neuron a part of a circuit & recording the activity it is capable of.
In addition to this we need to copy the normal function in a human neuron. Human induced pluripotent stem cell (hiPSC) technology offers an exciting potential solution allowing us to create human neurons from skin samples of human donors. This provides a more relevant system in human neurons in which to study human disease; making this the gold standard.
At its core, this research aims to assess the changes in electrical communication that occur at an early stage in PD. By regularly sampling hiPSC neurons from PD patients, I propose to map changes to neuronal circuits over time during PD progression. In addition, I will also use genetic PD mouse models to verify these changes in more complex systems, and directly look at the effects these changes have on behaviour. I will use drugs to reverse these early neuronal changes, & see which prevent cell stress at later ages. Finally, we will look at "at-risk" individuals before the onset of PD symptoms to look or the same early changes in neuronal function by using non-invasive imaging techniques.
This strategy tackles PD by identifying early targets via the combined efforts of academia and drug companies, the use of cutting-edge technology in state-of-the-art models and the study of these systems over time. This will improve the effectiveness of PD treatment, importantly informing us when to treat.

PD is the fastest growing non infective global pandemic (Dorsey et al. 2018). Thus there is an incredibly great need to tackle it, with a worldwide benefit. The data from this fellowship will focus on improving understanding of when & how the earliest possible phenotypes converge & begin to cause dysfunction. When this is understood, specific phenotypes can be targeted at specific times during the disease progression. This will increase the effectiveness of therapeutics & clinical trials, & thereby improve the lives of those individuals with PD.
It is important to note that whilst the main risk factor for PD is age, the disorder is not a disease of the elderly but instead starts much earlier with very subtle effects. Thus, it is of great import to make longitudinal assessment of human neurons, to investigate when & how the disorder should be tackled. With that being the focus of this proposal, the evidence produced will benefit five major groups: At risk individuals, academics in medical research, pharma, NHS & medical services & government funders.
In the first instance, individuals who are at risk of developing PD will benefit from the data gathered here. Drugs identified by this study to alter early "prodromal" synaptic deficits & halt later pathology, have the potential to prevent the disorder & could be potentially tested in the latter phases of this study.
Currently translation of academic data to therapeutic design & its use in the clinic is ineffective. This may be a specific result of models & age/time-points often being under considered in clinical trials; thus, potentially valuable drugs may be disregarded as ineffective. By taking a considered longitudinal approach to assess the impact of early deficits on late degeneration (not normally possible with other shorter fellowship applications) my proposal will aid in the best use of data produced by academia. It aims to improve the dialogue between NHS/medical services, pharma & academics via direct interaction of the consortium (aimed to be generated in the fellowship) with the medical field. Finally, by improving clinical design the cost for pharma (by increasing the effectiveness of therapeutics) will be reduced.
In relation to this, the cost of care for a household with a member with PD can be as much as £16,582 per year according to Parkinson's UK reports. When coupled with the annual ~£30 million invested in clinical trials, it amounts to a large financial burden on the state. This cost is extremely high when you consider that (as previously stated) previous therapeutics are likely useful, but have been discarded due to testing on an inappropriate cohort, at an inappropriate timepoint. This fellowship endeavours to address these two major problems with the aim of improving current methodologies.
The impact of the project outcomes will manifest across each sector (public, private, 3rd) at different rates as the data is published. At the end of the 7-year project we would hope to be in a position to start clinical trials. Having identified synaptic alterations & compounds capable of modulating them (using compounds from AstraZeneca in iPSC & animal models) we will be able to start extrapolating these changes to prodromal (REM sleep Behaviour Disorder) PD human participants. Since results would involve calculations of predicted onset & measurements of actual onset, a 10-20 year window for results would seem feasible. In the short term, with publications of synaptic changes across models & extrapolated to humans during the 7-year proposal, there should be a change in perception of the importance of synaptic research & in particular, longitudinal experimentation in PD in the academic research community. Such changes in perception & publications would increase the effort of charities to fund both synaptic & longitudinal studies increasing the drive towards investigation of early dysfunction as opposed to late stage degeneration.