The role of astrocytes in early pathogenesis of motor neuron disease: a mechanistic study of neuronal degeneration and synaptic alterations

Motor neuron disease (MND) is a rapidly disabling condition, leading to generalized muscle weakness and finally to death most commonly by paralysis of breathing muscles. The patients' quality of life is significantly reduced during the median survival time of three years not only by physical disabilities but also by dementia to a variable degree. In the UK 1 in 300-500 people are at risk of developing this disease, affecting about 5000 people at any time. It is untreatable and there is urgent need to develop successful therapies. In order to achieve this we need to understand the problems occurring in nerve cells, called neurons and also in their surroundings.

The immediate issue causing disability is within motor neurons, specialized nerve cells that normally convey electrical impulses to achieve muscle contraction. However, a major breakthrough in MND research identified that glial cells involved in supporting the function of neurons can be diseased too. Astrocytes, a type of glial cell that closely interact with motor neurons, have been shown to directly harm or to disrupt important cross-talk between them, resulting in muscle weakness. These mechanisms commonly occur in MND, providing a logical target for new treatments.

Over the last decade as a researcher and practicing neurologist, my work was based on understanding the dialogue between astrocytes and neurons. Establishing a research group at the University of Cambridge, we have made fundamental observations supporting the idea that by default astrocytes are meant to repair damaged motor neurons. Now, I also assembled innovative collaborations to develop my skill-set and to use state-of-art models relevant to human disease to identify what goes wrong in the astrocyte and motor neuron relationship. The ultimate aim of this work is to gain insight that can help us to treat (and even possibly cure) MND.

The overarching aim of my proposal is to explore emerging AC-mediated pathomechanisms in MND with a view to identify novel and common targets for this incurable disease. This is immensely relevant and timely as alternative therapies require precise understanding of non-neuron dependent processes that may contribute to MN pathology. ACs have a central and shared role in non-cell autonomous MN degeneration. However, the lack of precise understanding of basic adaptive versus pathogenic responses have put AC centred therapeutic discovery on hold, in part, due to inadequate tools. Therefore my objectives are to reveal alterations of AC response to MN damage and its impact on MNs, integrating state-of-art human and mouse models of MND. Specifically, my related goals are to examine whether 1) AC intracellular signalling, in particular STAT3 pathways, relevant for neuroprotection and communication is disturbed; 2) communication specifically via AC processes and exosome mediated communication are perturbed; 3) altered AC interactions worsen intrinsic MN/synapse degeneration. These will be addressed in patient derived hiPSC-AC or AC-MN co-cultures carrying SOD1 or C9ORF72 mutations, covering a major pathological spectrum of MND, in addition to being the two major genetic forms. Using transgenic SOD1/GFAP-Cre mouse slice cultures provide a further advantage of AC-specific genetic manipulations and simultaneous functional assessments on ACs and MNs in an environment simulating in vivo pathology. The two complementary systems provide a powerful platform to discover alterations to recently discovered key regulator pathways in neuromodulation, including Ca2+-oscillation in astrocytic processes. Integrating functional observations with AC and MN specific RNA-sequencing will help mine transcriptome-wide data using a priori hypotheses. I anticipate that this will increase the yield of discovery and facilitate the development of desperately needed novel therapies.

Through addressing novel pathomechanisms in translationally relevant models I predict my research has a broad impact on multiple academic and non-academic beneficiaries both directly and indirectly.

Basic scientists and clinicians specialising in neurodegeneration research may be directly affected by my research output via dissemination in high impact open access journals, national and international conferences. The spread of knowledge may speed up other groups' work and may accelerate the clinical translational process, providing multiple channels for my group's research to impact. Clinicians with an interest in designing clinical trials and pharmaceuticals therefore could benefit by being inspired translational achievements or directly by using our published data. Our databases will be also publically available for scientists, and meta-analysis could facilitate the former group to achieve their goals. I anticipate that my overall communications process with public engagement, social media and educational forums will facilitate building enduring trust between scientists and the lay public so that we can form partnership in defining new priorities for future engagement and research agendas.

There is also a potential impact of my research on the health of patients, more directly by our findings in our clinically relevant translational platforms but also indirectly via a possible global effect of knowledge dissemination that may accelerate discovery. Even partial results in slowing disease progression of patients could contribute to the decrease on impact on individuals such as family and carers and the global socio-economic impact with a financial burden of £ 373 million in the UK. The new initiative by the Cambridge Drug Discovery Centre with pharmaceutical links has the potential of facilitating the translational progression of our research.