The axon in health and disease: Regulating molecular motors and presynaptic function

Abstract

Our brain, one of our most complex organs, allows us to move, feel, think and learn. The brain is built up from billons of brain cells, which together form a dynamic and complex network that processes all sorts of information. Each brain cell, also called neuron, receives information from thousands of other neurons via its multiple processes called dendrites. Only a single process, called the axon, is responsible for the transfer of this integrated information to other neurons via electrical signals. To transmit this information properly, the axon contains several unique structures and features. One of these unique structures are the presynaptic specializations which, together with the postsynaptic specializations located on the dendrites of receiving cells, form the synaptic connections where the transfer of signals takes place. The presynapses are important for conveying information to connected neurons via the release of neurotransmitters. These chemical signals are stored inside synaptic vesicles within the presynapse which fuse with the presynaptic membrane upon the arrival of an electrical signal which bind and activate receptors on the postsynapse of the receiving neuron. Therefore, proper functioning of presynapses is essential for accurate communication within the brain. The importance of the correct functioning of our synapses is highlighted by the numerous brain diseases associated with disrupted synapse function. Therefore this thesis is aimed to investigate the fundamental mechanisms of presynapse functioning to contribute to a better general understanding of presynaptic function on a molecular level In addition to presynapses, intracellular transport is also important for proper axonal functioning. Due to the significant length of the axon and since most of the cellular materials are produced in the cell body, active transport of these materials is essential to deliver the correct materials to the correct location within the axon. This active transport is carried out by molecular motor proteins, including kinesins, which transport specific cellular materials via the microtubule cytoskeleton, the roads of the cell. In addition, some kinesins play important functions in regulating microtubule dynamics. Therefore, the activity of kinesins need to be tightly controlled to ensure their activity or non-activity at the proper moments and locations. Therefore, this thesis is aimed to investigate the mechanisms of kinesin regulation and its relevance for normal neuronal development and shows how disrupted kinesin regulation contributes to the development of two different neurological disorders. In short, this thesis describes the fundamental processes needed for proper axonal functioning where we specifically focus on the mechanisms involved in presynapse functioning and the regulation of motor proteins. The importance of these molecular processes for the correct functioning of our neurons, and thus our brain, is highlighted by the many brain diseases implicated with disrupted functioning of both synapses and motor protein related processes. This thesis provides new insights into the molecular processes involved in presynaptic functioning and motor protein regulation. These insights will further contribute to our understanding of axonal functioning, in health and disease.