Parkinson’s Disease

Alpha-Synuclein and Structural Analysis

Alpha-synuclein is a key protein implicated in Parkinson’s Disease. We study its structural properties and aggregation dynamics, providing insights into the molecular basis of the disease.

Stephens, A.D., Kölbel, J., Moons, R., Chung, C.W., Ruggiero, M.T., Mahmoudi, N., Shmool, T.A., McCoy, T.M., Nietlispach, D., Routh, A.F. and Sobott, F., 2023. Decreased water mobility contributes to increased α‐synuclein aggregation. Angewandte Chemie International Edition, 62(7), p.e202212063.

Stephens, A.D., Zacharopoulou, M., Moons, R., Fusco, G., Seetaloo, N., Chiki, A., Woodhams, P.J., Mela, I., Lashuel, H.A., Phillips, J.J. and De Simone, A., 2020. Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity. Nature communications, 11(1), p.2820.

Alpha-Synuclein and Mitochondrial Dysfunction

Our research explores how alpha-synuclein disrupts mitochondrial function, leading to neuronal damage and neurodegeneration.

Lautenschläger, J. and Schierle, G.S.K., 2019. Mitochondrial degradation of amyloidogenic proteins—A new perspective for neurodegenerative diseases. Progress in neurobiology, 181, p.101660.

Lautenschläger, J., Wagner-Valladolid, S., Stephens, A.D., Fernández-Villegas, A., Hockings, C., Mishra, A., Manton, J.D., Fantham, M.J., Lu, M., Rees, E.J. and Kaminski, C.F., 2020. Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies. Journal of Biological Chemistry, 295(30), pp.10138-10152.

Alpha-Synuclein at the Presynapse

We examine how alpha-synuclein influences neurotransmission, investigating its role in synaptic activity and connectivity.

Lautenschläger, J., Stephens, A.D., Fusco, G., Ströhl, F., Curry, N., Zacharopoulou, M., Michel, C.H., Laine, R., Nespovitaya, N., Fantham, M. and Pinotsi, D., 2018. C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction. Nature communications, 9(1), p.712.

Stephens, A.D., Zacharopoulou, M. and Schierle, G.S.K., 2019. The cellular environment affects monomeric α-synuclein structure. Trends in biochemical sciences, 44(5), pp.453-466.

Lautenschläger, J., Kaminski, C.F. and Schierle, G.S.K., 2017. α-Synuclein–regulator of exocytosis, endocytosis, or both?. Trends in cell biology, 27(7), pp.468-479.

Fusco, G., Pape, T., Stephens, A.D., Mahou, P., Costa, A.R., Kaminski, C.F., Kaminski Schierle, G.S., Vendruscolo, M., Veglia, G., Dobson, C.M. and De Simone, A., 2016. Structural basis of synaptic vesicle assembly promoted by α-synuclein. Nature communications, 7(1), p.12563.

Stephens, A.D., Villegas, A.F., Chung, C.W., Vanderpoorten, O., Pinotsi, D., Mela, I., Ward, E., McCoy, T.M., Cubitt, R., Routh, A.F. and Kaminski, C.F., 2023. α-Synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased lipid-associated fibril uptake into iPSC-derived neurons. Communications Biology, 6(1), p.526.

Collaborations

Through interdisciplinary collaborations, including with Dr Jonathan Phillips (University of Exeter, UK), Prof. Frank Sobott (University of Leeds, UK), Prof Alfonso De Simone (University of Naples Federico II, Italy), and Dr James Ross (University of Leeds, UK), we advance knowledge in Parkinson’s disease mechanisms.