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PD-MitoQUANT – A quantitative approach towards the characterisation of mitochondrial dysfunction in Parkinson's disease

Periodic Reporting for period 2 - PD-MitoQUANT (PD-MitoQUANT – A quantitative approach towards the characterisation of mitochondrial dysfunction in Parkinson's disease)

Reporting period: 2020-02-01 to 2021-01-31

More than one million people live with Parkinson’s in Europe and this number is forecast to double by 2030. New, more effective treatments are urgently needed. While there are treatments which help improve some Parkinson’s symptoms, they do not improve all symptoms, nor do they slow or prevent disease progression.

Research has advanced our understanding of neurodegenerative diseases (NDs) like Parkinson’s, but better understanding of key disease processes and improved disease models are needed to develop better therapies. Mitochondria are the ‘powerhouses’ of the cell, but also contribute to cell death and neurodegeneration when they malfunction. There is considerable evidence that mitochondrial dysfunction is involved in Parkinson’s, but no effective treatments have been developed based on this knowledge. Researchers and companies developing new drugs need to know more about how mitochondrial dysfunction is involved in disease progression and new disease models need to be explored for drug discovery and development.

PD-MitoQUANT is an Innovative Medicines Initiative (IMI) project that brings together academic experts, small and medium-sized enterprises (SMEs), pharmaceutical companies from the European Federation of Pharmaceutical Industries and Associations (EFPIA) and patient advocacy organisation Parkinson’s UK to:
(i) deepen our understanding of mitochondrial dysfunction in Parkinson’s,
(ii) identify and validate molecular drivers and mechanisms in Parkinson’s, and
(iii) discover innovative therapeutic targets that can be further progressed by the EFPIA partners in the future.

PD-MitoQUANT assembles world-leading experts in mitochondrial function, cellular and in vivo models of Parkinson’s, advanced imaging, data-driven machine learning, and systems modelling. The team uses innovative techniques to investigate the role of a key protein, alpha-synuclein (αSyn), in Parkinson’s. The team explores how pathological aggregation of this protein impacts on mitochondrial dysfunction and aims to identify novel targets linked to mitochondria function for new treatments of Parkinson’s and potentially also other NDs. PD-MitoQUANT is also developing new models to study Parkinson’s and building on existing consortium expertise by applying cutting edge technologies, such as super-resolution imaging, innovative microfluidics and 3D ‘Organ-on-a-Chip’ (OrganoPlate®).
Work in the first two years has focused on developing and standardising key models, protocols and assays and applying them to study mitochondrial dysfunction in Parkinson’s.

αSyn is a protein normally found in neurons and other cells, but in Parkinson’s and other NDs, it builds up and forms aggregates that affect how neurons work. There are many forms of pathological αSyn, so the consortium first had to choose which form to use. p91 αSyn fibrils were selected as application potently induced aggregation of endogenous αSyn in the mouse brain or neurons cultured in vitro. High quality, well characterised batches of p91 fibrils were manufactured and distributed to partners.

Three different cell models of Parkinson’s have been optimised - primary cortical and dopaminergic neuron models, using harmonised cell culture protocols and treated with p91 αSyn fibrils; and a model using human neurons derived from induced pluripotent stem cells (iPSCs) obtained from a Parkinson’s patient with three copies of SNCA, the αSyn gene linked to Parkinson’s. Work is also under way to establish a second model of human neurons generated directly from the iPSCs (induced neurons), and a 3D ‘Organ-on-a-Chip’ (OrganoPlate®) platform is being optimised.

Four in vivo models have been established within the consortium. Two mouse models have been developed in partner labs. In one model, the levels of αSyn in the brain are increased by viral overexpression of human αSyn. In the other, injection of p91 αSyn fibrils causes aggregation of the endogenous αSyn. Models using fruit flies and roundworms have also been established by introducing αSyn genes into these model organisms. The short lifespan makes these species suitable for rapid and comprehensive validation and exploration of targets identified in the mammalian models.

Partners are now looking at how aggregation or increased levels of αSyn affects mitochondrial function. Applying specific functional assays to investigate how mitochondria produce and consume energy, partners have identified reduced energetic capacity and altered calcium signalling in neurons. Experiments also measured changes in neuronal firing in these conditions, mitochondrial protein import, and uptake of the neurotransmitter dopamine. 2D and 3D high-resolution imaging of mitochondria in all models has now started. The mitochondrial pathology caused by pathological αSyn is also being studied in different brain regions, with a decrease in an important mitochondrial complex already observed. Finally, an automatic pipeline for combined analysis of high-throughput ‘omics data has been developed to identify master regulators and signalling pathways involved in the observed mitochondrial dysfunction.
PD-MitoQUANT is an ambitious public-private partnership, bringing together academic experts, SMEs, EFPIA companies and the patient advocacy organisation Parkinson’s UK to improve our understanding of mitochondrial dysfunction in Parkinson’s, identify and validate molecular drivers and mechanisms, and discover innovative therapeutic targets for future exploration. The project will advance the state of the art by characterising and quantifying links between mitochondrial dysfunction and neurodegeneration, improving our understanding of NDs, and identifying novel regulators and therapeutic targets. PD-MitoQUANT will also revitalise industrial R&D in therapies for NDs by providing new knowledge, targets and tools to facilitate progress in this challenging field; opening new avenues for therapy development.

A coherent innovation management strategy, which balances the protection of commercially valuable IP with open access to academic and industrial R&D communities is in place to ensure maximal impact of the project. Protected results will encourage investment in future work by the EFPIA partners, building on the initial IMI2 investment. SMEs will ‘stress test’ their technologies in a non-competitive, open innovation environment, enabling integration of new knowledge to enhance their products/services and opening new markets. For example, GENEXPLAIN has updated its commercial databases, TRANSFAC, TRANSPATH and HumanPSD, with additional information about Parkinson’s. Published insights, tools and other outputs will also stimulate other companies and research groups to focus again on NDs and their treatment.

Parkinson’s is an important societal challenge, significantly impacting on the lives of people with Parkinson’s, as well as carers and family members. The disease also consumes a growing share of healthcare budgets. In the long-term, PD-MitoQUANT will contribute to the development of treatments that prevent, cure or slow the effects of Parkinson’s, benefiting patients and carers, and reducing a growing burden on European and global healthcare systems. PD-MitoQUANT includes two people with Parkinson’s, who keep these potential long-term benefits at the forefront, sharing their personal experiences of living with the disease and their hopes for people with Parkinson’s in the future.
Overview of PD-MitoQUANT project
PD-MitoQUANT partners