Navigating the neuronal maze: Unraveling Microtubule Cytoskeleton Organization and Motor Protein Dynamics

The proper distribution of molecules within cells is fundamental to the functioning of the human body. While smaller cells rely on passive processes for molecular distribution, larger and more complex cells like neurons require active transport. Neurons have distinct compartments, with an axon to send signals and dendrites to receive them. Active transport distributes the molecules to their respective compartments. With certain neurodegenerative diseases we find molecules in the wrong compartments of the neuron. This thesis aims to investigate the underlying mechanisms that regulate this selective transport. Active transport relies on a road network formed by hollow tubes called microtubules, and the motor proteins that walk on these tubes carrying cargo. Not all motor proteins walk in the same direction, with some only entering the axon, while other are able to enter both the axon and the dendrites. Using advanced microscopy techniques, we mapped out different types of microtubule roads in the neuronal dendrite. We found on the outside of the dendrite a shell of more dynamic microtubules, with on the inside a more stable core. Secondly, we studied one specific type of motor protein that preferentially binds to stable microtubules. We found that this selectivity was mediated by a part of the motor protein that is known to interact with another microtubule binding protein. This second protein is enriched on stable microtubules and functions like a road sign and recruits the motor to the subset. Overall, this work contributes to our understanding of active transport within neurons and might help us understand its role in neurodegenerative disease.