The role of microRNA regulation in a Drosophila model of Huntington disease

The overall goal of this proposal is to determine the roles played by small non-coding RNAs in Huntington Disease (HD), an incurable neurodegenerative disease and the most common monogenic neuropathology in the developed world. HD manifests as a combination of motor, cognitive and behavioural features which deteriorate the patient's physical and mental abilities, ultimately leading to death. Recent studies in humans (Hoss et al., 2014) have demonstrated that many small non-coding RNAs (microRNAs, miRNAs) show differential expression in HD brains suggesting that miRNAs may be involved in the development of HD pathology or be part of a cellular compensatory mechanism that combats the disease. This project investigates these important and timely questions using a Drosophila model of HD.
The work will be focused on two central questions:
Q1: What are the molecular mechanisms that trigger miRNA dysregulation in HD?
Q2: What are the mechanisms that link HD-related miRNA dysregulation to neural dysfunction?
The project will be developed as a novel collaboration between Prof. Claudio Alonso at the University of Sussex and Prof. Gillian Bates, FRS at UCL. The Alonso lab is an international leader in the study of the neural roles of miRNAs in Drosophila and Prof. Bates is a world authority in the molecular cellular biology of HD and an expert in mammalian models of HD. The highly complementary nature of our team puts us in an excellent position to determine the roles played by miRNA regulation in a Drosophila model of HD while keeping close to the context of mammalian models of this disease. The project fits the core remit of the MRC Neuroscience and Mental Health Board on "understanding of the mechanisms of neurodegeneration and disorders of the motor system" and will also contribute to advance current models on the molecular control of "the physiology of the nervous system in health and illness".

Huntington Disease (HD) is an incurable disease that causes a combination of motor, cognitive and behavioural features which deteriorate the patient's physical and mental abilities, ultimately leading to death. Recent studies in humans revealed that several small non-coding RNAs (microRNAs) show differential expression in HD brains suggesting that microRNAs may be involved in the development of HD pathology or constitute a compensatory mechanism by the patient. This project investigates these important and timely questions using a Drosophila model of HD. In preliminary work to this application we discovered that induction of HD in Drosophila leads to dysregulation of a common minimal microRNA "signature" associated to HD in both humans and flies. In addition, overexpression of one signature HD-microRNA upregulated in HD (miR-10) in a non-HD background is sufficient to trigger severe locomotor defects in adult flies, while attenuation of miR-10 function in HD flies significantly improves locomotor defects. These observations show that Drosophila is an excellent genetically-tractable system where to study the mechanisms that link microRNA dysregulation to HD. This proposal builds on this and investigates (i) the mechanisms that link HD to microRNA dysregulation, and (ii) the neural cellular basis underlying microRNA effects on motor dysfunction. The project will be developed as a novel collaboration between the labs of Professor Claudio Alonso (an international expert in microRNA neurobiology at the University of Sussex) and Professor Gillian Bates FRS, a world leader in the molecular and cellular biology of Huntington Disease from UCL. The work will thus contribute to two MRC core objectives in relation to neuroscience research: (i) fundamental discovery research relating to the development, function and disorders of the human nervous system, and (ii) research to inform novel strategies for preventing and treating disorders of the nervous system.

The overall goal of this proposal is to determine the roles played by small non-coding RNAs in Huntington Disease (HD), an incurable neurodegenerative disease and the most common monogenic neuropathology in the developed world. HD causes a combination of motor, cognitive and behavioural features which deteriorate the patient's physical and mental abilities, ultimately leading to death. Recent studies in humans have demonstrated that a large number of small non-coding RNAs (microRNAs) show differential expression in HD brains suggesting that microRNAs may be involved in the development of HD pathology or constitute part of a cellular compensatory mechanism that combats the disease. This project investigates these important and timely questions using a Drosophila model of HD.
The proposal hits a core scientific remit of the MRC Neuroscience and Mental Health Board, i.e. "understanding of the physiology and behaviour of the human nervous system... as well as how to treat and prevent disorders of the brain". It belongs to the NMHB portfolio on "Neurodegeneration" and commitment to support work on "neurodegenerative conditions that result in progressive degeneration or death of nerve cells, including disorders of the motor systems".
We expect the project to have several potential avenues for impact. I. Who will benefit?
- Researchers working in basic neuroscience
- Researchers working in the medical application of neuroscience
- Patient groups suffering HD
- General public
II. How will they benefit?
(i) Academic beneficiaries. During the lifetime of the project, the main form of impact will be within the academic community. Several benefits can be envisaged:
-Training the new generation of scientists. Because the work will integrate modern molecular biology and neurodegeneration, a significant benefit will involve capacity building for postdocs, technicians and students, who may develop careers in industry or academia. New capacities will include skills in cutting-edge approaches in transcriptomics, neurophysiology, imaging and microscopy. These skills are applicable to clinical brain research, biomedicine, and data sciences.
- Promoting Interdisciplinary Research. The project has the potential to fuel new interdisciplinary research emerging at the interface between Molecular Biology and Brain Disease research catalysing the development of new technologies and approaches that emerge from principles of molecular biology and the neurophysiology of disease.
- Reducing Animal Experimentation. Our work will foster core principles of the "3Rs" the UK National Centre for the Replacement, Refinement and Reduction of animal use in research. NB: the use of Drosophila is promoted under the specific initiative of "partial replacement".
(ii) Beneficiaries of applications stemming from the project:
- Development of novel HD therapies. Our work has the legitimate long-term potential of identifying new targets for pharmacological manipulation with the view of ameliorating or eradicating symptoms of HD. This might impact the work of large pharmaceutical companies with core interests in neurodegeneration (GSK, Sanofi, Roche). Professor Bates will lead these efforts given that she is in contact with companies in this sector due to her on-going HD therapy evaluation work.
(iii) Patient groups suffering HD
- New ways of treating HD. Our work can unlock some of the fundamental processes that underlie the development and establishment of HD. Therefore, in the long-term, our work may open up the possibility that patients suffering from HD will be able to receive new forms of treatment.
(iv) General public
We will make extensive use of public engagement channels to share the implications of our work with the public, explaining how our science can contribute to decode the mechanisms of disease as detailed in the Communications Plan and Pathways to Impact.