PhD Studentship: The impact of altered axonal transport in novel humanised models of motor neuron disease

Project Title: The impact of altered axonal transport in novel humanised models of motor neuron disease

The molecular mechanisms causing neuronal death in amyotrophic lateral sclerosis (ALS), a major form of motor neuron disease, are poorly understood. Two key consequences of our incomplete understanding of ALS pathogenesis are the lack of effective treatments for this human disorder and the need for a step-change in strategies to fight the disease.

In work leading to this proposal, we uncovered alterations in the transport of several organelles in the axons of motor neurons at pre-symptomatic stages of ALS pathogenesis, suggesting that these impairments play a causative role in disease onset and progression [1, 2]. Crucially, we identified distinct classes of molecules able to restore axonal transport to physiological levels at early symptomatic stages of disease, thus demonstrating that these pathological changes are fully reversible and may be used in future therapies targeting motor neuron disease [3-5].

In this PhD proposal, novel mouse models expressing ALS mutants of human TDP43 and FUS at endogenous levels will be used to further investigate aberrant axonal transport mechanisms. These mice will also be used to explore whether p38 MAPKalpha [3], IGF1R [4] and RET [5] inhibition, together with other small molecules currently being tested in the laboratory, are able to restore physiological rates of transport, therefore constituting an effective therapeutic strategy to treat ALS.

The translational potential of these results will be tested using human iPSC-derived motor neurons carrying the same ALS mutations as those assessed in mice. The PhD student will monitor axonal transport in these human motor neurons and examine whether promising compounds rescue the identified transport impairments. Furthermore, these human motor neurons will be used to analyse molecular changes in the composition of key axonal organelles associated with the observed axonal transport deficits.

This combined approach will allow us to test the hypothesis that counteracting axonal transport deficits represents a novel, effective therapeutic strategy towards treating ALS.

The candidate:

Candidates should be creative and self-motivated with an interest in neuronal cell biology and the translation of basic discoveries in therapies for human neurological conditions. By the start of their appointment, applicants should have obtained a degree in neuroscience or biomedical science (or equivalent) and not be in possession of a PhD.

The selected candidate will be supervised, supported, and mentored by Prof. Giampietro (Gipi) Schiavo and Dr. James Sleigh at UCL. They will join a dynamic, friendly, yet driven research group at the Queen Square Institute of Neurology. Please do not hesitate to contact Prof. Schiavo for more information at giampietro.schiavo@ucl.ac.uk.

References:

[1] Sleigh JN, Rossor AM, et al. Nat Rev Neurol. 2019; 15:691-703.

[2] Tosolini AP, Sleigh JN et al. Acta Neuropath Comm. 2022; 10:121.

[3] Gibbs KL, Kalmar B, et al. Cell Death Dis. 2018; 9:596.

[4] Fellows AD, Rhymes ER, et al. EMBO Rep. 2020; 21:e49129.

[5] Rhymes ER, Tosolini AP, et al. Cell Death Dis. 2022; 13:584

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