Motor neuron disease also referred as Amyotrophic lateral sclerosis (ALS) is a rapidly progressive debilitating disease affecting upper and lower motor neurons with a median survival rate of 2-3 years. Currently, riluzole that extends survival by only 2-3 months, is the only globally approved drug. The well studied ALS genes include TDP-43, an RNA-binding protein localised within nucleus that regulate splicing and RNA metabolism. Loss of function (LoF) of TDP-43 leads nuclear mis-localisation and cytoplasmic aggregation which is a hallmark of 97% of ALS cases and indeed observed in other neurogenerative diseases such as FTD and Alzheimer’s. LoF TDP-43 leads to the generation of several cryptic exons on plethora of genes and have been observed to be denovo translated leading to non-functional protein products and may affect their natural function and altered signalling cascades (1). There is an unmet need to better understand the pathways and molecular consequences of loss of function (LoF) and gain of toxicity of TDP-43 in neuronal and glial cells which collectively has been implicated as a key feature of TDP-43 proteinopathies.

A PhD project is available to develop a knowledgebase of TDP-43 loss of function (LoF) mediated cryptic splicing, identification of cryptic peptides, development of ultra-sensitive assays for mechanistic understanding TDP-43 LoF biology.

This studentship provides a great opportunity to learn and employ human iPSC derived motor neurons and glial cell models (2), protein biochemistry, transcriptomics, quantitative proteomic analysis using state-of-the-art Ultra-sensitive mass spectrometry (Orbitrap Astral and tims-TOF SCP mass spectrometers), Bioinformatics, Proteogenomics (3) and targeted PRM mass spectrometry assays (4).

References:

1. Seddighi S, Qi YA, Brown AL, Wilkins OG, Bereda C, Belair C, et al. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD. Sci Transl Med. 2024:eadg7162.
2. Banerjee P, Mehta AR, Nirujogi RS, Cooper J, James OG, Nanda J, et al. Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration. Sci Adv. 2023;9(16):eabq0651.
3. Kim MS, Pinto SM, Getnet D, Nirujogi RS, Manda SS, Chaerkady R, et al. A draft map of the human proteome. Nature. 2014;509(7502):575-81.
4. Nirujogi RS, Tonelli F, Taylor M, Lis P, Zimprich A, Sammler E, et al. Development of a multiplexed targeted mass spectrometry assay for LRRK2-phosphorylated Rabs and Ser910/Ser935 biomarker sites. Biochem J. 2021;478(2):299-326.