Primary supervisor: Dr Kosala Dissanayake
Other supervisors: Prof Tom Wishart
Location: University of Edinburgh
Project description
The heterogeneous nature of motor neuron diseases (MND) including Amyotrophic Lateral Sclerosis (ALS) has been an obstacle to both understanding the causes of disease and development of more effective treatments. All the familial and sporadic forms of MND/ALS are linked by the clinical hallmark of ALS, which is muscle weakness caused by degeneration of motor neurons. Muscle denervation serves essentially as a reporter and amplifier of motor neuron loss (1).
We hypothesise that unique proteins in the blood of patients with MND/ALS arise from denervated muscle, in amounts that are proportional to the amount of muscle denervation (2). Thus, we aim to identify muscle-derived molecular biomarkers (3) in the blood that arise in response to motor neuron degeneration at neuromuscular junctions. First, we will measure molecular changes in muscle and blood samples in animal models of progressive partial denervation (axonal injury-induced denervation of muscle in healthy adult wild-type animals). Second, compare those with pre-symptomatic and symptomatic stages in a TDP43 mouse model of ALS. Finally, we compare the results of proteomic analysis in the first two stages with the molecular profile of blood samples from ALS patients. We anticipate data will be used to identify sensitive molecular markers of ALS will thus facilitate far earlier diagnosis of MND/ALS as well as an indicator of assessing disease progression in clinical trials of novel treatments (4,5).
References
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King PH. Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review. Neural Regen Res. 2024 Apr;19(4):747-753. PMID: 37843208.
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Sturmey E, Malaspina A. Blood biomarkers in ALS: challenges, applications and novel frontiers. Acta Neurol Scand. 2022 Oct;146(4):375-388. PMID: 36156207; PMCID.
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Kline RA, Lößlein L, Kurian D, Aguilar Martí J, Eaton SL, Court FA, Gillingwater TH, Wishart TM. An Optimized Comparative Proteomic Approach as a Tool in Neurodegenerative Disease Research. Cells. 2022 Aug 26;11(17):2653. PMID: 36078061.
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Malaspina A. Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers. Int Rev Neurobiol. 2024; 176:171-207. PMID: 38802175.
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Verber NS, Shepheard SR, Sassani M, McDonough HE, Moore SA, Alix JJP, Wilkinson ID, Jenkins TM, Shaw PJ. Biomarkers in Motor Neuron Disease: A State-of-the-Art Review. Front Neurol. 2019 Apr 3; 10:291. PMID: 31001186.
Suitable first degree subjects
Any biomedical degree including (not exhaustive) molecular biology, neuroscience, physiology
Essential/desirable skills and experience
Desirable to be familiar with molecular biology techniques
