Superresolution Microscopy in Parkinson's Disease - Linking Mitochondrial Dysfunction and Alpha-Synuclein Misfolding
Final Report Abstract
The characteristic hallmark of Parkinson’s disease (PD) is the occurrence of Lewy bodies, protein aggregates which mainly consist of alpha-synuclein. This project aimed to understand how mitochondrial dysfunction, another major keyplayer in PD, impacts on the homeostasis of alphasynuclein. We demonstrated that mitochondrial dysfunction clearly links to alpha-synuclein aggregation, however the downstream effects of mitochondrial dysfunction, including oxidative stress, increased cytosolic calcium, and complex I inhibition were not able to influence alpha-synuclein aggregation upon seeding with pre-formed fibrils (PFF). Rather, we show that the seeding propensity of alpha-synuclein aggregation is dependent on mitochondrial proteostasis, where we identified the mitochondrial HtrA2 and Lon proteases and mitochondrial protein import as crucial keyplayers. Furthermore, we showed that alpha-synuclein is imported into mitochondria, indicating a possible direct role of mitochondria in protein degradation, demonstrating a new perception on how we think about the role and occurrence of mitochondrial dysfunction in protein misfolding diseases. However, the finding that calcium had no effect on the seeding of alpha-synuclein aggregation was unexpected, as calcium is able to increase alpha-synuclein aggregation in vitro. One possible explanation is that in our model system using PFFs, the aggregation process is mainly driven by fibril elongation, thus limiting conclusions on the initiation of new aggregation events. On the other side, we show that calcium has a direct effect on the binding of alpha-synuclein to synaptic vesicles. While alphasynuclein was known to bind to synthetic lipid vesicles via its N-terminal region, we demonstrated here that the C-terminal region of alpha-synuclein also interacts with synaptic vesicles, which is regulated in a calcium dependent manner. Furthermore, calcium was shown to influence the localization of alphasynuclein within the presynaptic terminal. Thus, calcium could be a crucial factor for the physiological function of alpha-synuclein in regulating synaptic vesicle homeostasis and exo- and endocytosis.
Publications
- Alpha-synuclein - regulator of exocytosis, endocytosis or both? Trends Cell Biol; 2017, Vol. 27 (7), P. 468-479
Lautenschläger J, Kaminski CF, Kaminski-Schierle GS
(See online at https://doi.org/10.1016/j.tcb.2017.02.002) - An easy-to-implement protocol for preparing postnatal ventral mesencephalic cultures. Front Cell Neurosci; 2018, Vol. 12, P. 1-10
Lautenschläger J, Mosharov EV, Kanter E, Sulzer D, Kaminski Schierle GS
(See online at https://doi.org/10.3389/fncel.2018.00044) - C-terminal calcium binding of alpha-synuclein modulates synaptic vesicle interaction. Nat Commun; 2018, Vol. 9, P. 712
Lautenschläger J, Stephens AD, Fusco G, Ströhl F, Curry N, Zacharopoulou M, Michel CH, Laine R, Nespovitaya N, Fantham M, Pinotsi D, Zago W, Fraser P, Tandon A, St Georg-Hyslop P, Rees E, Phillips JJ, De Simone A, Kaminski CF, Kaminski Schierle GS
(See online at https://doi.org/10.1038/s41467-018-03111-4)
