PhD: Nervous system stability in health and disease

Nottingham Trent University offers a fully funded PhD using mass spectrometry and post mortem human brain tissue to find why some brain regions are more vulnerable to neurodegeneration.

Through the human lifespan, the nervous system grows, develops, stabalises and in some regions begins to decline. The factors governing the stability of the nervous system as we age, and indeed its susceptibility to neurodegeneration inducing stimuli remain unclear.

Many neurodegenerative conditions share a range of common pathophysiological hallmarks such as cellular accumulation of abberent and/or missfolded protein and/or metabolic byproducts, and regionally selective neuronal loss. Neurodegeneration can be caused by a range of potential inititating factors from clear cut genetic triggers, through to envenoming toxins. The onset of such neurodegenerative conditions can be associated with advancing age such as Alzheimer’s disease, frontotemporal dementia, vascular dementia, and dementia with lewy bodies to name a few examples for which there are few genetic associations. They can also occur as dementias of childhood (i.e. Batten disease, Neimann-Pick, Sanfilippo syndrome etc) which are all genetically mediated. One of the key questions in neurodegenerative research is what is it about certain brain regions which makes them more or less susceptible to a neurodegeneration inducing stimuli?

The project proposed here would aim to identify specific protein cascades which correlate and (in some cases) regulate neurodegenerative disease processes invivo. At NTU we have state of the art mass spec capabilities, invivo and human tissue resources which would allow us to address this.

The successful applicant would have the opportunity to shape the project as it develops and would receive appropriate training in experimental design including the use of post mortem human tissues, sample handing and preparation for mass spec, handling large data sets, pathway analysis including predicting potential regulators hubs, and invivo work with simple model organisms.

Supervisory team

1. Prof. Tom Wishart
2. Dr Keeley Brooks
3. Dr Shreyasi Chatterjee

References

• Haploinsufficiency of lysosomal enzyme genes in Alzheimer’s disease. Benitez et al. bioRxiv [Preprint]. 2024 Nov 18:2024.11.16.623962. doi: 10.1101/2024.11.16.623962. PMID: 39605615
• Necroptosis inhibition counteracts neurodegeneration, memory decline, and key hallmarks of aging, promoting brain rejuvenation. Arrázola et al. Aging Cell. 2023 May;22(5):e13814. doi: 10.1111/acel.13814. Epub 2023 Mar 27. PMID: 36973898
• Synaptic proteomics reveal distinct molecular signatures of cognitive change and C9ORF72 repeat expansion in the human ALS cortex. Laszlo et al. Acta Neuropathol Commun. 2022 Oct 29;10(1):156. doi: 10.1186/s40478-022-01455-z. PMID: 36309735
• Temporal Profiling of the Cortical Synaptic Mitochondrial Proteome Identifies Ageing Associated Regulators of Stability. Graham et al. Cells. 2021 Dec 2;10(12):3403. doi: 10.3390/cells10123403.PMID: 34943911
• Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype. Hesse et al. Acta Neuropathol Commun. 2019 Dec 20;7(1):214. doi: 10.1186/s40478-019-0847-7. PMID: 31862015