Amongst the commonalities of neurodegenerative diseases such as Parkinson's disease (PD), are bioenergetic failure and oxidative stress, both of which reflect the dysfunction of mitochondria within neural and glial cells. As such, a detailed understanding of mitochondrial dysfunction in the brain in the context of ageing, injury by misfolded protein toxicity, and genetic factors associated with neurodegeneration holds much promise for the development of therapeutic interventions that could impact multiple neurodegenerative disease states.
The overall challenge of the topic is to develop an unprecedented appreciation of the evolution of mitochondrial dysfunction in models of PD in order to understand if dysfunction is a driver of disease progression. A key goal is to develop an unprecedented appreciation of mitochondrial function in an in vivo model of neurodegenerative disease, which is currently lacking. Other challenges to be addressed within this topic are to quantitatively dissect changes in mitochondrial function in in vitro and in vivo models (including brain slices) and through mechanistic computational models of PD; and to understand the impact on the degeneration of neurons and/or glia.
There is a growing appreciation of the impact of glial cells (astrocytes, oligodendrocytes and microglia) in neurodegeneration, so it would be valuable to investigate mitochondrial dysfunction in several cell types. There is also the opportunity to investigate mitochondrial function in neural cells derived from human sources, both from patients and unaffected individuals.
Identification of the key molecular drivers of mitochondrial dysfunctions in the disease models will provide a unique scaffold to enable the discovery and development of new therapeutics to halt neurodegenerative disease progression.
It is anticipated that the topic will lead to the identification of key molecular drivers which will provide a foundation for the identification and validation of new drug targets, facilitating innovative therapeutic approaches within the neurodegeneration field. Moreover, mitochondrial abnormalities serve as a connecting theme between several neurodegenerative diseases, with a direct link to several processes known to be impaired in neurodegeneration such as bioenergetics and misfolded protein toxicity. Therefore, the learnings are anticipated to also feed into the understanding of the role of mitochondrial dysfunctions in other neurodegenerative diseases such as Alzheimer’s disease (AD).
The overall scope of the project generated by this topic is to identify and understand the impact of mitochondrial dysfunction in in vitro and in vivo models of neurodegenerative diseases, incorporating core characteristics of neurodegeneration such as protein misfolding. Understanding if dysfunction is a driver of disease progression, and the detailed mechanisms responsible for it, will enable the exploration of novel targets for therapeutic approaches to neurodegenerative diseases.
The scope will be reached by a scientifically robust strategy building on established and innovative PD models, and the appropriate technology experience within the consortium. More specifically, this will include addressing the following objectives:
Progressive neurodegenerative diseases represent a large and growing burden. Despite a considerable investment in research aimed at understanding and treating neurodegeneration, the lack of disease-modifying therapies remains notable. Recognising this gap, the treatment of neurodegenerative disease is a clearly-identified goal of IMI2 JU, and the expected impact of the project to be generated by this topic is closely aligned with the overall goal.
There is considerable evidence implicating mitochondrial dysfunction in the pathogenesis of a number of progressive neurodegenerative diseases, including Parkinson’s disease, but no efficacious treatments have been developed based on this knowledge.
By developing a set of validated cellular assays, organotypic brain slice models and in vivo tools, the project will remove an important barrier that has limited the systematic exploration of mitochondrial dysfunction in neurodegenerative disease. A clear identification of the specific mitochondria dysfunctions (such as respiratory function, biogenesis, trafficking, fission, fusion or mitophagy) contributing to neurodegeneration will enable the discovery of novel targets for intervention.
By taking advantage of recent advances in the understanding of mechanisms that control mitochondrial dynamics and using innovative technologies to access mitochondrial dysfunction (e.g. axonal transport and fusion/fission in highly relevant model systems), this approach should provide unprecedented insights into the causal link between mitochondrial dysfunction and neurodegeneration.
SMEs can be of great benefit to IMI2 JU projects and, inter alia, strengthen the competitiveness and industrial leadership of Europe. Their involvement might offer a complementary perspective to industry and academia, and help deliver the long-term impact of the project. For these reasons, applicants should consider engaging SMEs throughout the proposal.
The project learnings will strongly aid neurodegenerative disease understanding and the identification of novel targets, giving academics/SMEs/pharmaceutical companies new options for treatments of diseases with mitochondrial dysfunction, such as PD. Moreover it would encourage a renewed investment in developing drugs for neurodegenerative disorders for which there is a high unmet medical need. In particular, biotech SMEs will be able to ‘stress-test’ their technologies in a non-competitive, open innovation environment, which will greatly facilitate the development of novel and important therapeutics.
Thus, it can be anticipated that the results of the project will benefit patients and society through the accelerated discovery of new drugs and therapies for neurodegenerative diseases.