Our group studies mechanisms of brain health, ageing and disease focusing on the lysosomal protein transmembrane protein 106B (TMEM106B) which forms amyloids in the brain in an age-dependent manner. TMEM106B genetic variants have also been found to modulate healthy ageing and disease risk in frontotemporal lobal degeneration (FTLD) and Alzheimer’s disease. However, the underlying mechanisms behind TMEM106B and its implications for ageing and neurodegenerative disease are as yet, unknown.
TMEM106B has been implicated in various lysosomal processes. Lysosomes are highly dynamic organelles, present at the crossroads of cell signalling, transcription, and metabolism. Their role was initially understood to be key to degrading cellular waste, though understanding of lysosomes have since expanded, and it is now established that they are also intrinsic to ageing and neurodegeneration. We will use multidisciplinary approaches to shed new insights into the role of lysosomal TMEM106B in ageing and neurodegeneration. Ultimately, this advanced understanding will help identify new avenues of research in lysosomal biology in the context of ageing and may lead to the development of new therapeutic strategies to slow the processes of ageing and neurodegeneration.
Available projects will utilise a range of cell biology, structural and biochemical models of ageing and neurodegeneration. It is expected that the student’s interests will contribute to the direction of the project. For further information contact Dr. Diana Arseni- email: darseni@mrc-lmb.cam.ac.uk.
References
Schweighauser, M., Arseni, D., Bacioglu, M., Huang, M., Lövestam, S., Shi, Y., Yang, Y., Zhang, W., Kotecha, A., Garringer, H.J., Vidal, R., Hallinan, G.I., Newell, K.L., Tarutani, A., Murayama, S., Miyazaki, M., Saito, Y., Yoshida, M., Hasegawa, K., Lashley, T., Revesz, T., Kovacs, G.G., Swieten, J.v., Takao, M., Hasegawa, M., Ghetti, B., Spillantini, M.G., Ryskeldi-Falcon, B., Murzin, A.G., Goedert, M., Scheres, S.H.W. (2022)
Age-dependent formation of TMEM106B amyloid filaments in human brains
Nature 605(7909): 310-314
Arseni, D., Nonaka, T., Jacobsen, M. H., et al.
Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C. (2024) Nature. In press
Arseni, D., Chen, R., Murzin, A.G., Peak-Chew, S.Y., Garringer, H.J., Newell, K.L., Kametani, F., Robinson, A.C., Vidal, R., Ghetti, B., Hasegawa, M., Ryskeldi-Falcon, B. (2023)
TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP
Nature 620(7975): 898-903
Arseni, D., Hasegawa, M., Murzin, A.G., Kametani, F., Arai, M., Yoshida, M., Ryskeldi-Falcon, B. (2022)
Structure of pathological TDP-43 filaments from ALS with FTLD
Nature 601(7891): 139-143
Yang, Y., Arseni, D., Zhang, W., Huang, M., Lövestam, S., Schweighauser, M., Kotecha, A., Murzin, A.G., Peak-Chew, S.Y., Macdonald, J., Lavenir, I., Garringer, H.J., Gelpi, E., Newell, K.L., Kovacs, G.G., Vidal, R., Ghetti, B., Ryskeldi-Falcon, B., Scheres, S.H.W., Goedert, M. (2022)
Cryo-EM structures of amyloid-β 42 filaments from human brains
Science 375(6577): 167-172
Tetter, S., Arseni, D., Murzin, A.G., Buhidma, Y., Peak-Chew, S.Y., Garringer, H.J., Newell, K.L., Vidal, R., Apostolova, L.G., Lashley, T., Ghetti, B., Ryskeldi-Falcon, B. (2024)
TAF15 amyloid filaments in frontotemporal lobar degeneration
Nature 625(7994): 345-351