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Dissertation zugänglich unter
URN: urn:nbn:de:gbv:18-91525
URL: http://ediss.sub.uni-hamburg.de/volltexte/2018/9152/


Spastin regulates microtubule dynamics and is required for normal motor and cognitive functions

Teixeira Lopes, André

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Freie Schlagwörter (Deutsch): Spastin , microtubule , neuronal transport , synapse , memory
Freie Schlagwörter (Englisch): Spastin , microtubule , neuronal transport , synapse , memory
Basisklassifikation: 42.20 , 42.61 , 42.13 , 42.15 , 42.61
Institut: Biologie
DDC-Sachgruppe: Biowissenschaften, Biologie
Dokumentart: Dissertation
Hauptberichter: Kneussel, Matthias (Prof. Dr.) , Lohr, Christian (Prof. Dr.)
Sprache: Englisch
Tag der mündlichen Prüfung: 23.06.2017
Erstellungsjahr: 2017
Publikationsdatum: 31.05.2018
Kurzfassung auf Englisch: The distribution of membrane proteins to specific subcellular domains poses particular challenges to the protein trafficking machinery of nerve cells. Most transmembrane proteins are transported over long distances from the soma into axons and dendrites. This intracellular transport is driven in an ATP-dependent manner by kinesin and dynein motor proteins along microtubules.
Microtubules are polymeric cytoskeletal structures with variable lengths, which can grow or shrink resulting in a dynamic cellular network. Neurons contain both stable and dynamic pools of microtubules that can be regulated by microtubule severing proteins. Spastin, a member of AAA ATPase family, encoded by the SPAST gene, is one of these severing proteins expressed in neurons.
Microtubule function can be modulated by microtubule associated proteins and different post-translational modifications of tubulin subunits. Notably, tubulin polyglutamylation promotes microtubule severing through spastin.
Here, I used a mouse model lacking spastin to analyze the role of microtubule severing proteins regarding motor protein-dependent transport of glutamate receptors. In hippocampal spastin knockout neurons, I observed increased microtubule stability and altered microtubule dynamics. Additionally, the transport of glutamate receptors was diminished. Consequently, glutamate receptor levels at the cell surface were significantly reduced. Behavioral analysis showed impaired motor performance and specific learning and memory deficits in spastin knockout mice.
These data suggest that microtubule severing provides an important mechanism to maintain the cell surface delivery of synaptic proteins. This might explain the cognitive deficits observed in mice lacking the microtubule-severing protein spastin.

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