Hereditary spastic paraplegias (HSPs) are a group of progressive neurodegenerative conditions characterized by spasticity of the lower limb muscles due to progressive axonopathy of the longest upper motor neurons of the corticospinal tract leading to gait impairment. HSP affects over 20,000 people in Europe, yet there are currently no effective treatments and the progressive loss of motor neuron function is irreversible (https://en.wikipedia.org/wiki/Hereditary_spastic_paraplegia).

Recent work with the O’Sullivan lab has found that HSP-causing mutation disrupt lipid organisation within fly and cell models of HSP (Byrne et al., 2022). Specifically, disease-causing mutations in neurons triggers lipid accumulation in the glia surrounding long motor neuron axons. Importantly, we have found that disrupted lipid homeostasis is pathophysiologically relevant in our fly models of HSP as treatment with lipid regulating drugs rescues neurodegenerative phenotypes. It is essential to uncover the mechanism by which lipid homeostasis is disrupted in HSP and to ascertain whether targeting this pathway offers potential as a novel therapeutic strategy for treatment of disease in patients.

In this PhD project, you will work in both the O’Sullivan (https://fniamhy.wixsite.com/osullivanlab) and Murphy (https://people.ucd.ie/keith.murphy) research groups at University College Dublin to generate and investigate novel Drosophila and iPSC models of HSP. You will employ CRISPR and transgene expression technologies to modify lipid homeostasis in a cell-type-specific manner, perform confocal microscopy to examine changes in neuronal and glial organisation, and identify mechanisms to modify disruption caused by HSP-causing mutations. This work will:

a) Provide high impact insights into the fundamental role of lipid homeostasis within axons by generating synergistic findings in both flies and human models

b) Clarify how HSP-causing mutations give rise to axonal degeneration   

Conditions:

• Start date: March 2023 

• Full EU fees + €18,500 per annum stipend over four years.

• Each student will be enrolled in a Structured PhD programme, associated with the School.

• Each student is required to demonstrate in appropriate laboratory practicals as part of their scholarship conditions.  Demonstrating hours and lab practicals are detailed and assigned by the SBBS Demonstrating Committee (maximum hours: 288 per annum).  Research Scholars will be paid by the hour for demonstrating.

• The student and his/her supervisor are required to submit an application for an IRC Postgraduate Scholarship in the first year of their SBBS-funded research scholarship.

• The scholarship has to be taken up by the end of Spring trimester 22/23, otherwise the Scholarship will lapse.

• While no consumables budget is automatically applied to these scholarships, the School will endeavour to make modest sums available to supervisors with Research Scholars over the course of their scholarship.

Enquiries and applications (to include cover letter and CV) to Associate Professor Niamh O’Sullivan. Email: niamh.osullivan@ucd.ie.

Closing date: Friday 16th December, 2022.