In this grant, we propose to understand role of kinesins in axonal transport and synapse formation. Because of the extraordinary length of axons, synaptic vesicles and active zone proteins need to be transported over long distance on microtubules to reach the distal axon where synapses form. Our previous work showed that the entry and exit of synaptic cargoes into and from the kinesin transport system are important regulatory steps for control the location of synaptogenesis and the size of synapses. Here, we use genetic, biochemical, biophysical and cell biological method to directly understand how UNC-104/KIF1A is regulated in vivo to achieve specific loading and unloading of synaptic cargoes. We will also study how force generation of kinesins impacts the transport system by perturbing force generation and studying the consequence of such perturbations. We will also study how the distinct functions of two kinesins in trafficking synaptic cargoes. Through these experiments, we hope to provide mechanistic understandings of how the KIF1A family of kinesin motors is controlled in vivo. We also hope to provide insights in the biological meaning of regulated force generation. Since axonal transport defects has been recognized as early pathological progression of neurodegenerative diseases, these molecular understandings can potential lead to therapeutic innovations.
Axonal transport is critical to the health of neurons. Mutations in the kinesin-3 family motors were found in hereditary neuropathy such as hereditary spastic paraparesis. There is also a body of evidence that defects in axonal transport in aging neurons cause trafficking jams, which are early signs of neurodegenerative disease state. In this grant, we aim to understand the molecular mechanisms that regulate kinesin activity in vivo. The knowledge about how motor proteins are regulated will potentially lead to therapeutic strategies against neurodegenerative diseases.
|Niwa, Shinsuke; Tao, Li; Lu, Sharon Y et al. (2017) BORC Regulates the Axonal Transport of Synaptic Vesicle Precursors by Activating ARL-8. Curr Biol 27:2569-2578.e4|
|Krieg, Michael; Stühmer, Jan; Cueva, Juan G et al. (2017) Genetic defects in ?-spectrin and tau sensitize C. elegans axons to movement-induced damage via torque-tension coupling. Elife 6:|
|Niwa, Shinsuke; Lipton, David M; Morikawa, Manatsu et al. (2016) Autoinhibition of a Neuronal Kinesin UNC-104/KIF1A Regulates the Size and Density of Synapses. Cell Rep 16:2129-2141|
|Yogev, Shaul; Cooper, Roshni; Fetter, Richard et al. (2016) Microtubule Organization Determines Axonal Transport Dynamics. Neuron 92:449-460|
|He, Jiang; Zhou, Ruobo; Wu, Zhuhao et al. (2016) Prevalent presence of periodic actin-spectrin-based membrane skeleton in a broad range of neuronal cell types and animal species. Proc Natl Acad Sci U S A 113:6029-34|
|Li, Pengpeng; Merrill, Sean A; Jorgensen, Erik M et al. (2016) Two Clathrin Adaptor Protein Complexes Instruct Axon-Dendrite Polarity. Neuron 90:564-80|
|Maro, Géraldine S; Gao, Shangbang; Olechwier, Agnieszka M et al. (2015) MADD-4/Punctin and Neurexin Organize C. elegans GABAergic Postsynapses through Neuroligin. Neuron 86:1420-32|