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Unravelling the role of interneurons in Amyotrophic Lateral Sclerosis


   School of Psychology

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  Dr Ilary Allodi, Dr Susana Aznar  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

In ALS, motoneuron degeneration leads to muscle paralysis. Motoneurons are the final output of the brain since they directly connect to muscles, but their synchronized activation depends on networks of spinal interneurons. We recently showed that in the ALS mice, a subpopulation of inhibitory interneurons is affected early in disease. Inhibitory interneurons lose their synapses on motoneurons, and degenerate. This event can contribute to unbalanced excitability in motoneurons. Our data shows that stabilization of synapses between interneurons and motoneurons by over-expression of a presynaptic organizer, leads to increase motoneuron survival and amelioration of symptoms. However, to date, an approach to selectively target neuronal subpopulations by gene therapy in humans does not exist. Neither it is known if neuronal markers used to identify interneurons in the mouse spinal cord are expressed in human tissue. Thus, we will 1) validate molecular markers for spinal interneurons in human post-mortem tissue by spatial transcriptomics; 2) investigate the fate of interneurons in ALS post-mortem tissue; 3) produce new AAV-PHP.eB viruses carrying neuron-specific enhancers. The overall aim of this project is to generate novel tools for gene therapy. This will allow for non-invasive neurons-specific viral delivery, while decreasing off-target effects. These experiments could bring a novel therapeutic strategy to the field.

We are seeking students with a suitable first degree in molecular biology, neuroscience, medicine, biochemistry or a related discipline, ideally with the following desirable skills and experience:

Background in neuroscience

Genuine interest in neurodegenerative diseases, transcriptomics and gene therapy

Previous training in molecular biology techniques (qPCR, cell culture) and microscopy

Experience in tissue handling for mRNA and protein analysis

Previous experience in bioinformatics and knowledge of R/Python will be considered a plus

Fluent in English (written and spoken)

Ability to perform experiments and to interpret results

Strong background in ALS or other neurodegenerative disorders will be considered a plus

Willingness to learn new techniques

Well-organized, self-motivated, result-oriented and capable of working independently in a collaborative setting


Funding Notes

This studentship is offered as part of the Euan MacDonald Centre for Motor Neuron Disease Research. The Euan MacDonald Centre is a Scotland-wide network for MND researchers. For more about the Centre and the PhD scheme in particular please visit euanmacdonaldcentre.org/phd-scheme.
This studentship will be held at the University of St Andrews. Dr Allodi will be re-locating her lab to St Andrews in 2023.
The studentship will commence in Autumn 2023. It includes 3 years stipend payments at the standard UKRI rate, University tuition fees, and £5K per year for three years towards consumables and attendance at conferences and training courses.

References

Allodi I*, Montañana-Rosell R, Selvan R, Löw P, Kiehn O*. (2021) Locomotor deficits in a mouse model of ALS are paralleled by loss of V1-interneuron connections onto fast motor neurons. Nature Communications 12, 3251. *Co-corresponding
Allodi I, Nijssen J, Aguila Benitez J, Schweingruber C, Fuchs A, Bonvicini G, Cao M, Kiehn O, Hedlund E. (2019) Modeling motor neuron resilience in ALS using stem cells. Stem Cell Reports 12(6) 1329-41
Allodi I, Comley LH, Nichterwitz S, Nizzardo M, Simone C, Corti S, Hedlund E. (2016) Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS and SMA. Scientific Reports 16;6:25960.

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