The molecular mechanisms of clustered synaptic plasticity: focus on lysosomes
Final Report Abstract
The central aim of this research proposal is to test the hypothesis whether lysosomal positioning and exocytosis in dendrites plays a role in the establishment of clustered synaptic plasticity. This project builds up on the previous work performed in frame of the DFG Emmy Noether Program where we discovered new specialisations of dendritic actin cytoskeleton and showed that in principal neurons dense F-actin mesh surrounding excitatory shaft synapses served as a place for docking various secretory trafficking organelles. Thus, we could demonstrate that dendritic endolysosomes stall at the shaft synapses and that activation of actin motor myosin V leads to a long-term anchoring of the organelles. Here, we asked what is such lysosome positioning good for? In search for the answer, we explored non-conventional functions of neuronal lysosomes, such as exocytosis and control of dendritic mRNA translation. The preliminary data generated during implementation of this project led to two successful grant applications: a project within the newly funded DFG research unit 5228 “Membrane trafficking processes underlying presynaptic proteostasis” (project PI) and a project within the 2nd funding period of the DFG collaborative Research Center 1315 “Mechanisms and Disturbances in Memory Consolidation: From Synapses to Systems" (project co-PI together with Matthew Larkum and Volker Haucke). My group has moved to Berlin, and we established a lab at the Institute of Biology. Berlin’s scientific environment provided excellent settings for establishment of new networks and collaborations. Currently I am working on several projects dealing with the role of organelle and protein trafficking in synaptic plasticity, participating in teaching of bachelor and master’s courses (Experimental Biophysics and Optobiology), mentoring students and postdocs and actively involved in various scientific and administrative activities at the Humboldt University and the Charité. Taken together, this fulfils the main purpose of the Emmy Noether Program.
Publications
- In vivo regulation of the A disintegrin and metalloproteinase 10 (ADAM10) by the tetraspanin 15. Cell Mol Life Sci. 2018 Sep;75(17):3251-3267
Seipold L, Altmeppen H, Koudelka T, Tholey A, Kasparek P, Sedlacek R, Schweizer M, Bär J, Mikhaylova M, Glatzel M, Saftig P
(See online at https://doi.org/10.1007/s00018-018-2791-2) - F-actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes. J. EMBO J. 2019 Aug;38(15):e101183
van Bommel B, Konietzny A, Kobler O, Bär J, Mikhaylova M
(See online at https://doi.org/10.15252/embj.2018101183) - Myosin V regulates synaptopodin clustering and localization in dendrites of hippocampal neurons. J Cell Sci. 2019 Aug;132(16):jcs230177
Konietzny A, González-Gallego J, Bär J, Perez-Alvarez A, Drakew A, Demmers JAA, Dekkers DHW, Hammer JA 3rd, Frotscher M, Oertner TG, Wagner W, Kneussel M, Mikhaylova M
(See online at https://doi.org/10.1242/jcs.230177) - Radial F-actin organization affects growth cone dynamics during early neuronal development. EMBO Rep. 2019 Sep;20:e47743
Meka DP, Scharrenberg R, Zhao B, König T, Schaefer I, Schwanke B, Kobler O, Klykov S, Richter M, Eggert D, Windhorst S, Dotti CG, Kreutz MR, Mikhaylova M, de Anda FC
(See online at https://doi.org/10.15252/embr.201947743) - Cyclase-associated protein 2 dimerization regulates cofilin in synaptic plasticity and Alzheimer's disease. Brain Commun. 2020 Jun 26;2(2):fcaa086
Pelucchi S, Vandermeulen L, Pizzamiglio L, Aksan B, Yan J, Konietzny A, Bonomi E, Borroni B, Padovani A, Rust MB, Di Marino D, Mikhaylova M, Mauceri D, Antonucci F, Edefonti V, Gardoni F, Di Luca M, Marcello E
(See online at https://doi.org/10.1093/braincomms/fcaa086) - Enzyme replacement therapy with recombinant pro-cathepsin-D corrects defective proteolysis and autophagy in Neuronal Ceroid Lipofuscinosis. Autophagy. 2020 May;16(5):811-825
Marques ARA, Di Spiezio A, Thießen N, Schmidt L, Grötzinger J, Lüllmann-Rauch R, Storck SE, Pietrzik CU, Fogh J, Bär J, Mikhaylova M, Glatzel M, Bassal M, Bartsch U, Saftig P
(See online at https://doi.org/10.1080/15548627.2019.1637200) - Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses. Elife. 2021 May;10:e66165
Bucher M, Niebling S, Han Y, Molodenskiy D, Hassani Nia F, Kreienkamp HJ, Svergun D, Kim E, Kostyukova AS, Kreutz MR, Mikhaylova M
(See online at https://doi.org/10.7554/elife.66165) - Spike-timing-dependent plasticity rewards synchrony rather than causality. Cereb Cortex. 2021 Feb:bhac050
Anisimova M, van Bommel B, Wang R, Mikhaylova M, Simon Wiegert J, Oertner TG, Gee CE
(See online at https://doi.org/10.1093/cercor/bhac050) - Caldendrin and myosin V regulate synaptic spine apparatus localization via ER stabilization in dendritic spines. EMBO J. 2022 Feb;41(4):e106523
Konietzny A, Grendel J, Kadek A, Bucher M, Han Y, Hertrich N, Dekkers DHW, Demmers JAA, Grünewald K, Uetrecht C, Mikhaylova M
(See online at https://doi.org/10.15252/embj.2020106523) - Regulation of microtubule detyrosination by Ca2+ and conventional calpains. J Cell Sci. 2022 May;135(9):jcs259108
Bär J, Popp Y, Koudelka T, Tholey A, Mikhaylova M
(See online at https://doi.org/10.1242/jcs.259108)
