MRC DiMeN Doctoral Training Partnership: The role of endoplasmic reticulum-mitochondria contacts in neurodegeneration

Neurodegenerative disorders are complex, devastating diseases and a significant public health concern worldwide. Recent progress in the field has highlighted that although multiple molecular mechanisms underpin neuronal dysfunction, many of them converge on altered function of mitochondria and/or endoplasmic reticulum (ER). ER and mitochondria have interdependent functions and physically interact with each other at specialised contact sites, termed mitochondria-associated ER membranes (MAMs). These contact sites are essential for inter-organelle communication and their disruption has been implicated in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease and Charcot-Marie-Tooth disease (CMT).

The precise causes of ER–mitochondria contact site disruption in disease and the exact mechanism by which defects in ER–mitochondria communication underpin pathology of such diseases remains poorly understood. However, human mutations in genes that regulate ER–mitochondria contact sites have been shown to cause genetic forms of neurodegeneration, demonstrating the importance of ER–mitochondria crosstalk for neuronal function and survival and suggesting that targeting the underlying causes of disruption may be of therapeutic benefit. 

Charcot-Marie-Tooth disease (CMT) comprises a group of inherited progressive conditions causing motor and sensory neuropathies, resulting in muscle wastage, mobility issues and pain. The most common form of CMT type 2, CMT2A, is caused by mutations in mitofusin 2 (MFN2). MFN2 was originally discovered as a mitochondrial fusion factor but data from our labs and others has shown that MFN2 has a wider role in the regulation of mitochondrial dynamics, including axonal transport. Recent work has shown that MNF2 acts as a possible tether protein to regulate ER–mitochondria contacts. We and others have shown that ER–mitochondria contacts regulate mitochondrial dynamics but if this is also the case for MFN2 remains unclear.

The hypothesis we wish to address in this project is that human CMT2A mutations in MFN2 affect ER-mitochondria contacts leading to disruption of mitochondrial dynamics and function, and consequently neuronal death. 

We propose to test this hypothesis using a novel human pluripotent stem cell (hPSC) model of CMT2A, namely MFN2^R94Q/+ motor and sensory neurons that is already established in the laboratory of the first supervisor and the cellular and molecular ER-mitochondria and neurobiology assays established in the laboratory of the second supervisor.

This project uses stem cell maintenance and differentiation, coupled with state-of-the-art microscopy, physiological, biochemistry and molecular biology approaches, including the use of CRISPR/Cas9, electrophysiology, proximity ligation assays, and super-resolution fluorescence microscopy.

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

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