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Deep Learning-based Characterisation of Protein Aggregation in amyotrophic lateral sclerosis (ALS) (EPS2022/50)


   School of Engineering & Physical Sciences

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  Dr M Vallejo, Dr Y Altmann  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating neurodegenerative disease that affects motor neurons [1]. Patients develop progressive muscle weakness, leading to death due to respiratory failure, which typically occurs after 3–5 years of symptom onset. ALS affects 1.75 – 3 out of 100,000 individuals per year [2]. The existence of protein aggregates in affected motor neurons is still a poorly understood hallmark.

This project aims at increasing the understanding of these structures. To achieve this aim, the project intends to visualise them using super-resolution microscopy and apply different machine learning techniques to extend the understanding of the TDP-43 aggregates at an individual level. To approach this problem, a super-resolution image dataset was gathered at the University of Edinburgh from post-mortem tissue of ALS patients extracted from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) cohort [3].

Optical imaging is a powerful tool that can gain insights into TDP-43 aggregates' structure and assembly mechanisms. In particular, super-resolution microscopy can be used to observe the conformations of proteins in biological samples. However, their low concentration, high levels of heterogeneity, and the propensity to behave differently in cells compared to in vitro hinder their analytical study and general use [4]. This project aims at characterising in more detail how distinct species of aggregates and their distribution are presented in different cells and different patients.

How to Apply

1. Important Information before you Apply

When applying through the Heriot-Watt on-line system please ensure you provide the following information:

(a) in ‘Study Option’

You will need to select ‘Edinburgh’ and ‘Postgraduate Research’. ‘Programme’ presents you with a drop-down menu. Choose Chemistry PhD, Physics PhD, Chemical Engineering PhD, Mechanical Engineering PhD, Bio-science & Bio-Engineering PhD or Electrical PhD as appropriate and select September 2022 for study option (this can be updated at a later date if required)

(b) in ‘Research Project Information’

You will be provided with a free text box for details of your research project. Enter Title and Reference number of the project for which you are applying and also enter the potential supervisor’s name.

This information will greatly assist us in tracking your application.

Please note that once you have submitted your application, it will not be considered until you have uploaded your CV and transcripts.


Funding Notes

There are a number of scholarships available which offer funding from between 3 and 3.5 years at an average stipend rate of £15,000 per year.

References

[1] Ravits, J. M., and La Spada, A. R. (2009). ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology 73, 805–811. doi: 10.1212/wnl.0b013e3181b6bbbd
[2] Naruse, H., Ishiura, H., Mitsui, J., Takahashi, Y., Matsukawa, T., Tanaka, M., et al. (2019). Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS. J. Neurol. Neurosurg. Psychiatry 90, 537–542. doi: 10.1136/jnnp-2018-318568
[3] De Icaza Valenzuela, M.M., Bak, T.H., Thompson, H.E., Colville, S., Pal, S. and Abrahams, S., 2021. Validation of The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in behavioural variant Frontotemporal Dementia and Alzheimer's Disease. International Journal of Geriatric Psychiatry.
[4] Strohäker, T., Jung, B. C., Liou, S. H., Fernandez, C. O., Riedel, D., Becker, S., Halliday, G. M., Bennati, M., Kim, W. S., Lee, S. J. & Zweckstetter, M. (2019), ‘Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts’, Nature Communications 10(1), 1–12.
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