REGULATION OF ER-MITOCHONDRIA CONTACTS IN NEURODEGENERATION

In the brain, approximately 100 billion nerve cells allow us to think, remember, see, hear, speak etc. Inside of the nerve cells there are different compartments, called organelles. We call them organelles because for a cell they are more or less what an organ such as the liver is for the whole body. Organelles are surrounded by membranes; you can compare them to little balloons. Just as organs, organelles have specific functions. We are particularly interested in two of these organelles, called mitochondria and ER (ER is short for Endoplasmic Reticulum). Mitochondria are the organelles that convert the food we eat into a form of energy that the cells can use. They basically are the power stations of the body. The ER is the place in the cell where various building blocks of the cell, called proteins and lipids are made and then sent to specific places in the cell. Mitochondria and ER can swap energy and building blocks between them at places where the organelles touch. We call these places contact sites. It has become clear that when contact sites between ER and mitochondria are disrupted that this contributes to brain diseases such as motor neuron disease, dementia and Parkinson's disease. We don't know why this is so.
We have discovered a new mechanism that controls the amount of contact there is between the ER and mitochondria, and we believe that overactivation of this mechanism might be the reason that there is loss of contact in disease.
The purpose of this project is to investigate this new mechanism so that we can better understand what is going on. Once we know this we will try to use this knowledge to find new ways of restoring the contacts between the organelles. Once we can restore the contacts we can answer the question if this protects neurones in a dish from dying. Our hope is that this will be the case and that we can use what we learn in this project as the starting point to develop new drugs to treat brain diseases.

An estimated 5-20% of mitochondria are closely associated with a subdomain of the endoplasmic reticulum (ER) called mitochondria-associated ER membranes (MAMs). Inter-organelle communication at these contact sites has been shown to regulate several physiological processes including calcium homeostasis, autophagy/mitophagy, mitochondrial dynamics, phospholipid synthesis, the unfolded protein response, apoptosis, and inflammasome activation.
Disruption of ER-mitochondria contact sites has been implicated in amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) and Parkinson's disease (PD). We and others have shown reduced ER-mitochondria coupling in mutant SOD1, TDP-43, FUS, and Sigma-1R-associated ALS/FTD. Similarly, decreased ER-mitochondria contact has been reported in mutant a-synuclein-related PD.
The purpose of this proposal is to further our insight into the pathogenic pathways underlying ER-mitochondria contact defects in ALS/FTD and PD and to leverage that knowledge to validate ER-mitochondria contacts as a therapeutic target.
We have uncovered a novel kinase pathway that regulates ER-mitochondria contacts, and have data that suggest that upregulation of this pathway may be the underlying cause of ER-mitochondria contact disruption in SOD1-related ALS and a-synuclein-related PD.
We will further investigate this novel pathway and determine its involvement in ALS/FTD and PD. Building on this data we will validate ER-mitochondria contacts as a therapeutic target by determining if restoring contacts in ALS and PD models is neuroprotective and can improve disease-associated dysfunction.
This project may mark a crucial step in the translational pathway towards novel strategies to treat neurodegenerative conditions.

In the short term, the main impact of our research will be on the people employed on this grant, and academic and clinical researchers, particularly those with an interest in mitochondria, ER-mitochondria contacts, calcium homeostasis, autophagy/mitophagy, and neurodegeneration and ageing.
The continued employment and training of research staff involved in the project will benefit their careers both by learning specific research skills as well as a range of transferable skills such as analysis and problem solving, interpersonal and leadership skills, project management and organisation, information management, self-management, and written and oral communication. In a wider context, retaining and enhancing the training of skilled researchers benefits the UK.
The data generated and communications from this project will advance our understanding of the fundamental processes governing ER-mitochondria communication. This will inform new research and inspire academic and clinical researchers.
Furthermore, the overhead funding associated with this award will allow the Department and Faculty to further support and invest in the research facilities. Together with the purchase of the Odyssey Imaging System this will positively impact on the whole Sheffield research and student community.
In the medium to long term our research will have a wider impact and may benefit the pharmaceutical industry, the ageing population, patients with ageing-related neurodegenerative conditions and their families and society as a whole. Indeed, given that the endoplasmic reticulum and mitochondria are fundamental in both health and disease, the medium and long-term impact could be enormous.
Ageing-associated neurodegenerative disorders such as motor neuron disease (MND) and Parkinson's disease (PD)are devastating diseases with huge unmet medical need. The socio-economic impact of ageing-associated neurodegenerative conditions is set to rise significantly in the future because of the aging population. In addition to care provided within the NHS, a significant amount of care for patients takes place in the community, often with support of charitable organisations. Thus, these conditions place a huge public and private socio-economic burden on the UK.
Our research seeks to develop and validate novel targets that can be the basis for the development of novel classes of neuroprotective drug candidates and treatments for neurodegeneration and will motivate subsequent clinical studies. Our main objectives are to identify fundamental mechanisms associated with neurodegeneration and to provide proof-of-concept for novel therapies. If these therapies prove successful here, we will have discovered a new class of possible neuroprotective interventions in major neurodegenerative disorders including MND and PD.
The effect of better therapies will be most tangible for patients and their immediate families. Indeed, improving the symptoms and halting or slowing the progression of disease will have an enormous impact on their quality of life. In terms of economics this research could free up considerable resources in the NHS that are currently allocated to ageing-related disease and are set to rise in the future. Clearly the wider public would benefit from this. Furthermore, this work has the potential to influence government policy by reducing pressure on the health and social care systems and consequently allowing the refocusing of resources. As such this research may also impact on the public sector.
Our research may also have an economic impact via the commercialisation of our results and/or spinout companies. Business opportunities will be explored with the assistance of the University of Sheffield Research Services. At a local level, The University of Sheffield could benefit from licensing of any patents granted based on our findings, enhanced REF performance and increased reputation, which in turn would positively impact on our students and staff.