Mikrotubuli Dynamik in der Regulation postsynaptischer Struktur und Funktion: Rolle des Mikrotubuli Severing-Enzyms Katanin
Zellbiologie
Zusammenfassung der Projektergebnisse
Dynamic microtubules (MTs) regulate axonal and dendritic transport in neurons. They control mechanisms of synaptic function, including neurotransmitter release and synaptic plasticity as well as homeostatic processes. In addition to the polymerization and depolymerization of microtubules, MT severing contributes to sculpting and dynamically reorganizing MT arrays. Three major AAA-ATPases mediate MT severing in neurons, known as spastin, katanin and fidgetin. Katanin functions as a hexameric complex of dimers assembled through 60 kDa catalytic and 80 kDa regulatory subunits. In addition to its important role in cell division and adult neurogenesis, mammalian katanin regulates the number and length of neuronal MTs. Since microtubule severing enzymes have never been studied in the context of synaptic function and plasticity, we asked in this project whether katanin potentially contributes to synapse function. We found that katanin is abundant in dendrites and can be detected at actinrich spines and glutamatergic synapses. Following dominant-negative interference with katanin-mediated severing, we observed impairments in structural spine remodeling after glutamate uncaging and reduced MT polymerization into dendritic spines. Finally, functional inhibition of katanin affected the potentiation of AMPA-receptor-mediated excitatory currents after chemical LTP induction. In addition to the role of katanin at synapses, we checked whether other related severing enzymes regulate synaptic proteins. Our data reveal novel mechanistic insights into how spastin loss-of-function affects polyglutamylation and kinesin processivity, which in turn controls the transport of synaptic cargoes such as AMPA receptors. These parameters are critical in hippocampus-dependent working and associative memory in vivo. Together, our data demonstrate that microtubule severing is essential for the normal regulation of synaptic function and/or plasticity.
Projektbezogene Publikationen (Auswahl)
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Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits. PLOS Biology, 18(8), e3000820.
Lopes, André T.; Hausrat, Torben J.; Heisler, Frank F.; Gromova, Kira V.; Lombino, Franco L.; Fischer, Timo; Ruschkies, Laura; Breiden, Petra; Thies, Edda; Hermans-Borgmeyer, Irm; Schweizer, Michaela; Schwarz, Jürgen R.; Lohr, Christian & Kneussel, Matthias
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Katanin is involved in Microtubule Polymerization into Dendritic Spines and regulates Synaptic Plasticity. Cold Spring Harbor Laboratory.
Lombino, Franco L.; Schwarz, Jürgen R.; Pechmann, Yvonne; Schweizer, Michaela; Glatzel, Markus; Gee, Christine E.; Gromova, Kira V. & Kneussel, Matthias
