Role of microtubule turnover in cytoskeleton-mediated sorting and transport of synaptic proteins
Prof. Dr. Matthias Kneussel (2012 – 2017)
University Medical Center Hamburg-Eppendorf, ZMNH, Institute of Molecular Neurogenetics
Fundamental cellular functions, such as motility and division depend on the dynamic behavior of microtubules (MTs). MTs also regulate the sorting and transport of proteins to subcellular compartments inside cells. In neurons, the GluA2 subunit of AMPA receptors (AMPARs) is a key factor of excitatory synaptic transmission. Changes in postsynaptic AMPAR numbers contribute to long-lasting changes in synaptic strength including long-term potentiation (LTP) and long-term depression (LTD). To reach the synapse, GluA2 requires microtubule transport through the kinesin motor protein KIF5. We ask, whether and how the microtubule-severing enzyme spastin participates in the regulation of microtubule transport to synaptic sites. In humans, mutations associated with the spastin gene cause the most frequent form of autosomal dominant spastic paraplegia, an inherited disease whose main feature is progressive stiffness and contraction (spasticity) in the lower limbs, as a result of damage to or dysfunction of the nerves. Using conditional knockout of the AAA ATPase spastin in mice, we aim to investigate whether altered MT turnover affects receptor delivery and consequently synaptic function. Our project combines mouse genetics with live cell imaging and FRAP imaging in neurons. Cell biological studies at the neuron and synapse level are complemented with electrophysiology and the analysis of learning and memory.