EMC-2024-5_Sibley: Investigating the role of TDP-43 mis-splicing events in MND pathogenesis

   Centre for Clinical Brain Sciences

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  Dr C Sibley, Dr Matthew Horrocks  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This project is on offer as part of the studentship scheme of the Euan MacDonald Centre for Motor Neuron Disease Research. The Euan MacDonald Centre is a multi-disciplinary network of MND researchers across Scotland. A choice of six projects is on offer now for a start date in Autumn 2024, at the University of Edinburgh, St Andrews or Dundee. For more information see www.euanmacdonaldcentre.org/phd-scheme. Euan MacDonald Centre students join our network of >200 MND researchers across Scotland and will have the opportunity to meet people living with MND, participate in academic and public engagement events led by the Centre. To view all the projects offered under this scheme please search for reference numbers EMC-2024-1 to EMC-2024-6.

Approximately 98% of amyotrophic lateral sclerosis (ALS) cases display cytoplasmic TDP-43 aggregates, and several lines of evidence suggest parallel nuclear TDP-43 loss contributes to disease aetiology1. Nuclear depletion of TDP-43 leads to pre-mRNA splicing defects, and our novel analysis identified two mis-splicing events in genes with functions relevant to ALS initiation and progression. We have previously validated their TDP-43 dependence in human induced pluripotent stem cell (hIPSC) derived motor neurons (MNs), and found they led to associated pathway defects that in turn compromise TDP-43 homeostasis. Together this suggests these are important mis-splicing events that help drive initiation and progression of TDP-43 pathology. Correcting them may thus have translational potential.

Aim 1: In this project the student will first extend this work by using RNAscope and super-resolution imaging to quantify TDP-43 burden and mis-splicing of these events within patient post mortem tissue2. This will include in clinically significant areas of the CNS, and in tissues where we have shown TDP-43 pathology is detected pre-symptomatically3. Aim 2: Next, the student will design and validate lentiviral constructs to restore the loss-of-function of these two genes. Aim 3: Last, the student will test translational potential of their constructs in hIPSC derived motor neurons from ALS patients that display TDP-43 defects4, and in control lines depleted of TDP-43. The hypothesis is that these constructs will restore protein expression of these targets when nuclear TDP-43 levels are depleted, resolve associated pathway defects, and that this will delay or reverse TDP-43 homeostasis defects.

The student will join a team working around this theme within the Sibley lab, and gain experience in several molecular biology techniques and hIPSC modelling of disease. They will also train in advanced imaging approaches with the Horrock’s lab, and directly apply this to post mortem tissue samples. More broadly, the student will benefit from integration into the collaborative Euan MacDonald and Edinburgh Neuroscience networks where additional training opportunities will be presented.

Suitable first degree subjects: Neuroscience, Molecular biology, Biochemistry. Essential and/or desirable skills and experience: Essential: Molecular biology techniques (e.g. cloning, PCR, RNA extractions) Mammalian cell culture experience Fluorescent imaging (e.g. tissue or cells); Desirable: Experience with induced pluripotent stem cells Experience with human tissue handling.

Biological Sciences (4) Medicine (26)

Funding Notes

The studentship comprises 42 months (3.5 years) stipend payments at the standard UKRI rate, tuition fees and an allowance of £10K per year for three years for consumables and travel. The studentship is open to applicants worldwide. Students will register for the most appropriate degree programme at the University where the project is being offered. It is the applicants’ responsibility to ensure they meet the eligibility requirements for postgraduate study at their chosen University, in terms of academic achievements and English language proficiency.


1 Suk et al. The role of TDP-43 mislocalization in amyotrophic lateral sclerosis. Mol Neurodegener. 2020 Aug 15;15(1):45.
2 Spence H et al. RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS. BioRxiv pre-print 2023.
3 Pattle SB et al. pTDP-43 aggregates accumulate in non-central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis: a case series linking archival surgical biopsies with clinical phenotypic data. J Pathol Clin Res. 2023 Jan;9(1):44-55.
4 Hall et al. Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS. Cell Rep. 2017 May 30;19(9):1739-1749.

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