Title: Investigating synaptic health over time in Parkinson’s Disease to identify early-stage modifiable therapeutic targets
Funder: Medical Research Council

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% of over 65's; there is currently no effective treatment. Dopaminergic neuronal loss important in movement control and behaviour is hallmark in PD, and results in the classic clinical motor symptoms. Research has focussed on halting, preventing or bypassing cell death; from this research, the potent drug L-DOPA was developed. However, the effectiveness of the drug diminishes over time, and does not prevent further degeneration. My programme of research will use a longitudinal approach in genetically faithful PD models which will recapitulate the progressive nature of the disorder. This will allow identification of dysfunction prior, and contributing to, late-stage neuronal death, providing early druggable targets in at risk individuals, and creating interventive therapeutics, which will stop the disorder from ever manifesting. The focus of the work will be at the synapse and the fundamental role of neurons: electrochemical signalling and transduction as the likely place where dysfunction will manifest. To achieve this we will: 1: Study the development of pathophysiological deficits in PD, over time, using human iPSC neurons derived from patients with mutations causing late onset PD, similar in progression to sporadic PD (i.e. LRRK2 - G2019S; GBA - N370S) and allowing identification of exactly when pathogenic phenotypes manifest. Cutting-edge electrophysiological experiments incorporating patchSeq and optopatch will provide the central experimental focus of this work with supporting standard molecular such as western and immunocytochemistry for validation. 2: Validate human iPSC data (see 1) using relevant knock-in animal models (courtesy Prof. Farrer) proving the ability to assess complex circuitry and behaviour not replicable in in vitro systems. Assessment will include both cognitive and motor function at early (30-90 days) & late (365-540 days) stages (in collaboration with Lelos lab; Cardiff). Importantly, we will link synaptic network alterations to behavioural changes using GCamP technology, to study calcium fluctuation as a measure of network activity in awake mice (photometry; with Walton Lab, Oxford) whilst they perform behavioural tasks. 3: Use the models & targets identified in 1 & 2 we will screen a synaptic specific compound library (provided by AZ) to identify compounds that modulate early phenotypes & thus, ameliorate/prevent late stage pathology. By working with AZ to identify structural analogues & identifying off target effects in said models (with Lane Lab) these compounds could be used later in preliminary trials (See 5). Future work will involve the validation of the pathophysiological timeline (seen in 1) in other autosomal dominant pathogenic mutations (i.e. synuclein mutation (A53T) & triplication; in collaboration with Volta Lab, EURAC) as well as use of imaging techniques to assess early neurotransmission & network activity changes (identified in 1, 2 & 4) in Rapid eye movement (REM) sleep behaviour disorder patients known to convert to PD at an extremely high number (~80%). This step will be critical for translation of identified targets and therapeutics to human patients and critically, enabling the identification of a suitable “prodromal” PD group to perform trials in.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL