The Role of Retrograde Mitochondrial Signalling and Epigenetic Reprogramming in Glial Toxicity and Neuroinflammation in Progressive Multiple Sclerosis

The focus will be on understanding how mitochondrial stress triggers epigenetic changes that drive the transition of astrocytes to a dysfunctional disease-associated radial glia-like (DARG) phenotype, contributing to the chronic neuroinflammation of P-MS3. The candidate would gain expertise in various "-omics" technologies, gene editing, molecular biology, cell culture, and potentially in vivo techniques.

The study will utilize iNSCs derived from P-MS patients and controls, as well as post-mortem brain samples or access to publicly available human datasets (eg snRNAseq and ST) 1, 2, 4-8.

Aims

Methodologies will include:

1. Mitochondrial stress induction and manipulation: Using various stimuli to induce mitochondrial stress in iNSCs 23 and assess downstream signalling and mt-dsRNA release.
2. Retrograde signalling analysis^{9, 10}: Studying the pathways by which mitochondrial signals (including mt-dsRNA)²³ communicate with the nucleus and influence gene expression and epigenetic modifications¹¹ (e.g., using RNA-seq, ATAC-seq, ChIP-seq, MeDIP-seq).
3. Epigenomic profiling: High-resolution mapping of DNA methylation, histone modifications, and chromatin accessibility changes in iNSCs and DARGs, with a particular focus on genes and pathways related to inflammation and senescence².
4. Functional studies: Using CRISPR-Cas9 gene editing and other techniques to manipulate key genes involved in retrograde signalling and epigenetic changes.
5. In vivo validation: Prioritize thorough in vitro work using iNSCs to establish a robust mechanistic understanding of the processes before attempting in vivo validation with brain organoids (available in the lab)^{12, 13}. Consider in utero xenotransplantation¹⁴ only as a subsequent project if substantial in vitro progress justifies the additional challenges (eg if feasible, depending on project timeline and resources).

The overall goal is to establish a comprehensive model of how mitochondrial stress, retrograde signalling, and epigenetic alterations^{15, 22} work together to drive the transition to DARGs and to explore potential therapeutic targets to prevent or reverse this process.

Funding Notes

For academic year October 27/28;

Gates US applications (round 1) close 14th October 26, further information available via Gates Website; View Website

Cambridge Trust, Gates Cambridge (round 2) deadline 8th December 26 to be eligible for funding. If you apply after the funding deadlines you will not be eligible for the Cambridge Funding competition, please indicate in your application all the funding you are eligible for. You can also check funding search Search - Postgraduate Funding Search

Funding is not available for Lent or Easter 27 places as the funding deadline for these has already passed, you will need to have other funding in place to support your studies

References

Application portal link;
PhD https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnpdpcn/apply
Research MPhil https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnmpmds/apply

Please do try to get in contact directly with the supervisor should you want to discuss the project further.
If you do not hear back from the supervisor, you contact you can still include their name on the application as this will be sent to them to review as well as our committee.

Further reading

Key selected refs

1. Ionescu RBN, A.M.; Reisz, J.A.; Williams, E.C.; Prasad, P.; Dzieciatkowska, M.; Stephenson, D.; Suarez Cubero, M.; Pirvan, L.; Willis, C.M.; Peruzzotti-Jametti, L.; Fossati, V.; Edenhofer, F.; Leonardi, T.; Frezza, C.; Mohorianu, I. D’Alessandro, A.; Pluchino S. Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis. biorxv 2024. DOI: https://doi.org/10.1101/2024.01.16.575826.
2. Park B. NAM, Tsitsipatis D., Pirvan L., Prasad P., Lopez De Novales M.L., Whitten J., Culig L., Llewellyn J., Ionescu R.B., Willis C.M., Krzak G., Fan J., De S., Suarez Cubero M., Spathopoulou A., Peruzzotti-Jametti L., Leonardi T., Edenhofer F., Gorospe M., Mohorianu I., Pluchino S., Beerman I. Integrative single-cell analysis of neural stem/progenitor cells reveals epigenetically dysregulated interferon response in progressive multiple sclerosis. bioRxiv 2024. DOI: https://doi.org/10.1101/2024.02.09.579648.
3. Schirmer L, Schafer DP, Bartels T, et al. Diversity and Function of Glial Cell Types in Multiple Sclerosis. Trends Immunol 2021; 42: 228-247. 20210213. DOI: 10.1016/j.it.2021.01.005.
4. Absinta M, Maric D, Gharagozloo M, et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature 2021; 597: 709-714. 20210908. DOI: 10.1038/s41586-021-03892-7.
5. Schirmer L, Velmeshev D, Holmqvist S, et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 2019; 573: 75-82. 20190717. DOI: 10.1038/s41586-019-1404-z.
6. Alsema AM, Wijering MHC, Miedema A, et al. Spatially resolved gene signatures of white matter lesion progression in multiple sclerosis. Nat Neurosci 2024; 27: 2341-2353. 20241105. DOI: 10.1038/s41593-024-01765-6.
7. Lerma-Martin C, Badia IMP, Ramirez Flores RO, et al. Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions. Nat Neurosci 2024; 27: 2354-2365. 20241105. DOI: 10.1038/s41593-024-01796-z.
8. Kaufmann M, Schaupp AL, Sun R, et al. Identification of early neurodegenerative pathways in progressive multiple sclerosis. Nat Neurosci 2022; 25: 944-955. 20220620. DOI: 10.1038/s41593-022-01097-3.
9. Walker EM, Pearson GL, Lawlor N, et al. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues. Science 2025: eadf2034. 20250206. DOI: 10.1126/science.adf2034.
10. Butow RA and Avadhani NG. Mitochondrial signaling: the retrograde response. Mol Cell 2004; 14: 1-15. DOI: 10.1016/s1097-2765(04)00179-0.
11. A FCL. Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes. Clin Epigenetics 2020; 12: 182. 20201123. DOI: 10.1186/s13148-020-00976-5.
12. Simoes-Abade MBC, Patterer M, Nicaise AM, et al. Brain organoid methodologies to explore mechanisms of disease in progressive multiple sclerosis. Front Cell Neurosci 2024; 18: 1488691. 20241218. DOI: 10.3389/fncel.2024.1488691.
13. Birtele M, Lancaster M and Quadrato G. Modelling human brain development and disease with organoids. Nat Rev Mol Cell Biol 2024 20241212. DOI: 10.1038/s41580-024-00804-1.
14. Wu J, Greely HT, Jaenisch R, et al. Stem cells and interspecies chimaeras. Nature 2016; 540: 51-59. DOI: 10.1038/nature20573.
15. Santos JH. Mitochondria signaling to the epigenome: A novel role for an old organelle. Free Radic Biol Med 2021; 170: 59-69. 20201201. DOI: 10.1016/j.freeradbiomed.2020.11.016.
16. Ionescu RB, Nicaise AM, Reisz JA, et al. Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis. Cell Stem Cell 2024 20241014. DOI: 10.1016/j.stem.2024.09.014.
17. Nicaise AM, Wagstaff LJ, Willis CM, et al. Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proc Natl Acad Sci U S A 2019; 116: 9030-9039. 20190325. DOI: 10.1073/pnas.1818348116.
18. Papadopoulos D, Magliozzi R, Mitsikostas DD, et al. Aging, Cellular Senescence, and Progressive Multiple Sclerosis. Front Cell Neurosci 2020; 14: 178. 20200630. DOI: 10.3389/fncel.2020.00178.
19. Nicaise AM, Willis CM, Crocker SJ, et al. Stem Cells of the Aging Brain. Front Aging Neurosci 2020; 12: 247. 2020/08/28. DOI: 10.3389/fnagi.2020.00247.
20. Kular L, Klose D, Urdanoz-Casado A, et al. Epigenetic clock indicates accelerated aging in glial cells of progressive multiple sclerosis patients. Front Aging Neurosci 2022; 14: 926468. 20220824. DOI: 10.3389/fnagi.2022.926468.
21. Zhu X, Chen Z, Shen W, et al. Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention. Signal Transduct Target Ther 2021; 6: 245. 20210628. DOI: 10.1038/s41392-021-00646-9.
22. P Prasad, A Dugourd, AM Nicaise, CM Willis, M Miclaus, L Barea Moya, D Maddison, RB Ionescu, S Gil-Perotin, S Khoronenkova, JM Garcia Verdugo, E Avezov, A Von Kriegsheim, J Saez-Rodriguez, M Tigano, G Balmus and S Pluchino. Cytosolic mitochondrial RNA drives senescence and innate immunity in a patient stem cell model of progressive Multiple Sclerosis (manuscript in preparation).