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  EASTBIO: Power and co-ordination: the role of mitochondrial dysfunction in ataxia


   School of Medicine, Medical Sciences & Nutrition

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  Dr Guy Bewick, Dr Amy Vincent  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Supervisors:

Dr Guy Bewick - University of Aberdeen - Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition - [Email Address Removed]

Dr Amy Vincent - Newcastle University, Wellcome Centre for Mitochondrial Research - [Email Address Removed]

We want to understand why nerve endings sensing movement have such high densities of mitochondria. This project will study their precise functional importance. Ataxia (loss of movement fine control) frequently occurs with mitochondrial disease. This causes debilitating symptoms of falling and fear of falling. Mitochondrial malfunction is the main example of inherited diseases of metabolism. Mutations occur either in the mitochondrial genome or mitochondrial genes encoded in the nucleus, usually resulting in faulty energy production. Purely sensory ataxia is often an early symptom, with some studies showing it is the commonest symptom. This implies a possible specific role for mitochondria in sensory terminal function.

The sensory dysfunction, which includes cutaneous (skin) as well as proprioceptive (limb position) sensation, is due to peripheral neuropathy. This is classically said to affect nerve projections (axons) to/from muscles, but axons have low energetic demands and low mitochondrial abundance. However, dysfunction most likely affects cell areas where mitochondria are extremely abundant, i.e. sensory terminals. Our data show mitochondria occupy a striking 32% of the sensory terminal volume. This is ~6 – 10 times great than in skeletal muscle fibres, often regarded as a high mitochondria tissue. It even exceeds the density of heart muscle.

You will determine the abundance, distribution, structure and function of sensory-terminal mitochondria, using cutting edge serial block face scanning electron microscopy (SBF-SEM), electrophysiology of live tissue, pharmacology, immunohistochemistry and biochemistry of energy production. You will compare terminals in normal mice with those having mitochondrial DNA mutation, as well as between different types of sensory terminals (muscle, hair follicles & blood pressure sensors) which all have high mitochondria abundance. The project is based primarily in Aberdeen, benefiting from our many years of experience of studying these nerve terminals. Imaging in Newcastle will use their world-class expertise in SBF-SEM and biochemistry to understand the mitochondrial phenotype. They also have outstanding access to clinicians, clinical samples and data from the Newcastle Mitochondrial Disease biobank. You will train in their techniques and develop important networks during placements. Overall, from these comparisons of mitochondrial structure and function in normal, experimentally manipulated and diseased models, you will gain key insights into the important functional role of the very high mitochondrial density in nerve terminals at sites of movement detection, their role in ataxia, and potentially uncover therapeutic avenues for further treatment for mitochondrial diseases.

It may be possible to undertake this project part-time, in discussion with the lead supervisor, however please note that part-time study is unavailable to students who require a Student Visa to study within the UK.

Application Procedure:

Please visit this page for full application information: http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO application form, along with academic transcripts to Alison Innes at [Email Address Removed]

Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to [Email Address Removed]

Biological Sciences (4) Medicine (26)

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership.
This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition (limited funding is available to provide international tuition fees). Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.
Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject.

References

1. Ticci, C. et al. Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases. Journal of Clinical Medicine 10 (2021).
2. Faitg, J., et al.,. Mitochondrial morphology and function: two for the price of one! Journal of Microscopy 278, 89-106 (2020).
3. Bewick, G. S. Synaptic-like vesicles and candidate transduction channels in mechanosensory terminals. J. Anat. 227, 194-213 (2015).

Where will I study?

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